CN107964014A - 一种邻硝基芳酰化衍生物类化合物、制备方法及其应用 - Google Patents

一种邻硝基芳酰化衍生物类化合物、制备方法及其应用 Download PDF

Info

Publication number
CN107964014A
CN107964014A CN201711027851.5A CN201711027851A CN107964014A CN 107964014 A CN107964014 A CN 107964014A CN 201711027851 A CN201711027851 A CN 201711027851A CN 107964014 A CN107964014 A CN 107964014A
Authority
CN
China
Prior art keywords
compound
dmso
tms
nmr
ppm
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
CN201711027851.5A
Other languages
English (en)
Inventor
贺殿
祁生晓
杨林鹏
邓伟
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Lanzhou University
Original Assignee
Lanzhou University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Lanzhou University filed Critical Lanzhou University
Priority to CN201711027851.5A priority Critical patent/CN107964014A/zh
Publication of CN107964014A publication Critical patent/CN107964014A/zh
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明公开一种化合物，以及这种化合物的制备方法和其用途。本发明所述的化合物为如式Ⅱ中化合物d。本发明的化合物采用其他碘代方法以及酰氯法合成得到目标产物，共制备方法所需时间短，操作简单。相关的实验表明，本发明的化合物具有抗肿瘤活性，并具有对细胞的选择性高、毒性低的优点。

Description

一种邻硝基芳酰化衍生物类化合物、制备方法及其应用
技术领域
本发明涉及一种药用化合物及其制备和应用，确切讲本发明涉及一种抗癌用化合物—邻硝基芳酰化衍生物类化合物及制备方法及其应用。
背景技术
中国发明专利2013101816559公开一种邻硝基芳酰基β-氯乙基亚硝基脲类化合物，以及这类化合物的制备方法和用途，式中R为-COCH2C6H4NO2-o，或-COCH2CH2C6H4NO2-o，或-COCH2OC6H4NO2-o。本发明的化合物制备方法是以邻硝基芳香羧酸为合成原料，经酰化、取代、氯化和亚硝化得到目标化合物。本发明的化合物可在制备治疗肿瘤药物中的应用，特别是可在制备治疗乳腺癌药物或制备治疗恶性胶质瘤药物，或在制备治疗人宫颈癌药物或在制备治疗红白血病药物中的应用，但因鬼臼毒素临床应用缺点，特别是其对正常细胞的毒副作用，使其受到一定的限制。
发明内容
本发明公开一种如式Ⅰ示具有抗体癌活性的化合物—邻硝基芳酰化衍生物类化合物，其中：取代基R1为氢、氟、氯、溴、甲基或甲氧基；取代基R2为氢、
甲基、乙基或二甲基。
本发明所述的邻硝基芳酰化衍生物类化合物的制备方法是如反应式Ⅱ所示的方法制备，即：
1)将化合物a和无水碳酸钾加入溶剂DMF中并充分搅拌，再将化合物b
滴加到前述反应液中，加入催化量KI，在80～100℃搅拌充分反应，反应结束后分离出滤液，除去溶液DMF，残余物中加入NaOH至完全水解，再在其中滴加浓盐酸至固体不在析出，分离出滤渣用pH＝2～3盐酸水溶液冲洗，得到化合物c；
2)称取前一步骤得到的c，溶于干燥四氢呋喃中，加SOCl2和吡啶后70℃回流，旋蒸掉溶剂及过量SOCl2，得到酰氯，密封备用；
3)将4β-N-[(4-硝基苯基)哌嗪]-4′-去甲基表鬼臼毒素和三乙胺加入到干燥四氢呋喃中；在-20℃将步骤2)得到的酰氯缓慢滴加到前述四氢呋喃中，剧烈搅拌并在室温下充分反应后抽滤，滤液浓缩，所得残留物溶于二氯甲烷，分别用稀醋酸溶液，稀碳酸钠溶液以及饱和氯化钠溶液洗涤，合并有机层用无水NaSO4干燥，然后过滤，滤液经浓缩处理后用硅胶柱层析纯化，得到目标化合物d。
在上述的邻硝基芳酰化衍生物类化合物的制备方法中，优选的条件是：
步骤1)中是将10mmol化合物a和无水碳酸钾加入溶剂DMF中，并充分搅拌，再将12～15mmol化合物b滴加到前述反应液中，进行反应；
步骤2)中称取1.2mmol干燥化合物c溶于10mL干燥的四氢呋喃中，并向其中滴加两滴吡啶，然后缓慢的将3mmol的氯化亚砜滴入其中；
步骤3)中滤液用硅胶柱层析纯化时是以体积比为300/100/1的石油醚/乙酸乙酯/乙腈为洗脱剂。
本发明所述的邻硝基芳酰化衍生物类化合物的制备方法中的4β-N-[(4-硝基苯基)哌嗪]-4′-去甲基表鬼臼毒素制备方法可参见文献Jian-Fei Liu,Shi-Wu Chen,etal.Synthesis and evaluation ofthe cell cycle arrest and CT DNAinteractionproperties of4β-amino-4′-O-demethyl-4-deoxypodophyllotoxin s[J].Bioorganic&Medicinal Chemistry Letters,2013,21:6948-6955.，文献中记载的母体药物的合成是用鬼白毒素在甲基磺酸和碘化钠的作用下选择性去甲基，并且4位的构型翻转得到中间体4β-I-表鬼臼，后者再以干燥的三乙胺作为缚酸剂和1-(4-硝基苯基)哌嗪在干燥四氢呋喃中进行取代反应，从而得到目标化合物。但是，发现该方法最后得到的目标化合物的产率很低。所以，在实际的实验操作时，选择以表鬼臼毒素为原料，以碘化钾和三甲基氯硅烷作为碘代试剂在0℃下进行反应，其余反应步骤和文献记载相同，目标化合物的产率有所提高。此外，在实验过程中我们发现反应溶剂对产率影响较大。因此，我们主要对实验的反应溶剂进行了新的探索,我们最终选择乙腈作为反应的最佳溶剂，具体过程为：在冰浴条件下，将干燥的三甲基氯硅烷溶于无水乙腈后缓慢滴加到含去甲基表鬼臼毒素与碘化钠的无水乙睛中，经搅拌后加入无水碳酸钡再充分搅拌加入无水三乙胺数滴至反应液呈碱性后，加入化合物1-(4-硝基苯基)哌嗪，室温搅拌反应，反应完毕抽滤，滤液经浓缩处理，残留物中加入硫代硫酸钠溶液，用乙酸乙酯萃取，合并的有机层用无水硫酸钠干燥，然后过滤，滤液浓缩处理后经硅胶柱层析法纯化，以体积比为200/100/1的正己烷/乙酸乙酯/三乙胺为洗脱剂，得到化合物4β-N-[(4-硝基苯基)哌嗪]-4′-去甲基表鬼臼毒素。
本发明所述的邻硝基芳酰化衍生物类化合物通过与拓扑异构酶Ⅱ作用，形成易解离复合物.可防止DNA链再连接.导致双链DNA的断裂，进而破坏DNA结构，因此可在制备拓朴异构酶抑制剂药物中的应用。
本发明的邻硝基芳酰化衍生物类化合物在制备抗肿瘤药物中的应用。特别是在制备抗人非小细胞肺癌药物中的应用，或者是在制备抗人宫颈癌药物中的应用，或者是在制备抗人肝癌药物中的应用。
针对母体化合物4β-N-[(4-硝基苯基)哌嗪]-4′-去甲基表鬼臼毒素的毒性比较大、选择性低的缺点，本发明对母体进行了改造，经改造后的化合物对细胞的选择性高、毒性低。
本发明的化合物可在抗肿瘤药物的制备中应用，可以增大鬼臼类化合物对肿瘤细胞的选择性，减少细胞毒性。
由于鬼臼毒素的C-4位被含有氮的基团取代有助于提高该类化合物的抗肿瘤活性和水溶性以及哌嗪环具有良好水溶性以及等因素，本发明选择了以表鬼臼毒素为基础，C-4位被含有哌嗪环化合物取代的母体结构的化合物，邻硝基苯氧乙酸的侧链具有强吸电子的氧原子，氧原子具有2对未共用电子，与苯环发生共轭进行电子传递，C-O单键的存在限制构型的翻转，更有利于发生亲核性内酰化反应。此外，本发明模仿“三甲基锁”触发机制在药物理化性质改变、释放等发面优秀的表现，邻位引入得硝基基团可以利用肿瘤细胞与正常细胞的生理环境的差异，即肿瘤细胞中还原酶与水解酶含量较高，使所设计目标化合物进入肿瘤细胞后在硝基还原酶和酯水解酶的作用下，促使载体分子发生分子内环合，快速释放母体药物。从而达到改善鬼臼毒素类临床药物的耐药性以及毒副作用大的目的。本发明的目标化合物经取代、水解、酯化等反应逐步合成，本发明最终采用碘代方法以及酰氯法合成得到目标产物，该法所需时间短，操作简单，且产率基本在20％以上。化合物2b和2d不仅有较好的水溶性和脂溶性、抗肿瘤活性以及对正常细胞较低的抑制作用，在细胞凋亡和周期实验中也表现出较好的作用。
本发明目标化合物经取代、水解、酯化等反应逐步合成，本发明从鬼臼毒素临床应用缺点出发，利用正常机体细胞的微环境与肿瘤细胞相比有一定的差异性，肿瘤细胞中缺氧、pH低、一些特定的酶(比如水解酶和还原酶)活性较高等，设计合成了四种不同类型的邻硝基苯氧乙酸衍生物作为药物载体，以期提高化合物对肿瘤细胞的选择性，降低对正常细胞的毒副作用，并筛选最佳药物载体分子和效果最佳衍生物。本发明最终采用其他碘代方法以及酰氯法合成得到目标产物，共制备方法所需时间短，操作简单。将本发明的化合物分为四类，即：给电子效应组(d1-d6)、吸电子效应组(d7-d15)、空间效应组(d16-d19)、综合效应组(d20-d64)四类，用MTT法考察这四类衍生物对肿瘤细胞增殖抑制实验中，我们发现四类衍生物对A-549、Hela和Hep-G2三种癌细胞增殖均有较好的抑制作用，四类衍生物对Hela增殖抑制作用最好，其中d2和d5表现出最好的抑制活性；同时，与WI-38毒性实验对比发现，邻硝基芳酰化衍生物对正常细胞毒性较阳性对照低，表现出较高的选择性。
具体实施方式
本发明以下提供制备实施例及相应实验数据。
一、化合物制备实施例
1.载体分子c的合成
称取R1为3-CH3的化合物a110mmol，无水碳酸钾12mmol，加入到50mL圆底烧瓶中，量取25mL DMF作溶剂，室温搅拌30min；再量取R2为氢的化合物b120mmol，滴加到上述反应液中，加入催化量KI，将油浴锅升温至85℃，搅拌反应8-12h，TLC监测反应进度，反应毕趁热抽滤，取滤液；用真空油泵旋蒸掉DMF，残余物中加入20mL 0.03g/mLNaOH水溶液，室温搅拌至水解完全，滴加浓盐酸至固体不在析出，抽滤。滤渣用事先配制好的PH＝2-3盐酸水溶液冲洗，即得化合物c1。
同理可得R1和R2分别为式Ⅱ中其它取代基的c化合物。
2.母体药物的合成
在冰浴条件下，将干燥的三甲基氯硅烷4mmol溶于20mL无水乙腈中，并缓慢滴加到含去甲基表鬼臼毒素1mmol与碘化钠4mmol的无水乙睛40mL中，搅拌1h；加入无水碳酸钡3mmol，搅拌10分钟，再加入无水三乙胺数滴至反应液呈碱性后，加入化合物1-(4-硝基苯基)哌嗪1.2mmol，室温搅拌15小时；反应完毕抽滤，滤液减压浓缩，残留物中加入20％硫代硫酸钠溶液，乙酸乙酯萃取三次(20mL×3)，合并的有机层用无水硫酸钠干燥，然后过滤，滤液减压浓缩，得到的粗品经硅胶柱层析法纯化，以正己烷/乙酸乙酯/三乙胺(200/100/1)为洗脱剂，得黄色固体，即为母体化合物。
4β-N-[(4-硝基苯基)哌嗪]-4′-去甲基表鬼臼毒素的核磁共振谱如下：
1H NMR(400MHz,DMSO-d6,TMS,pm):δ8.26(s,1H),8.01(d,J＝8.0Hz,2H),7.36(s,1H),6.99(d,J＝8.0Hz,2H),6.49(s,1H),6.21(s,2H),5.96(d,J＝8.0Hz,2H),4.42(d,J＝4.0Hz,1H),4.05(dd,J1＝20.0Hz,J2＝12.0Hz,3H),3.58(s,6H),3.46-3.31(m,4H),3.02(dd,J1＝16.0Hz,J2＝4.0Hz,1H),2.57-2.45(m,5H).13C NMR(100MHz,DMSO-d6,TMS,ppm)：δ175.0,155.5,147.6(2C),147.5,147.1,137.4(2C),134.9,133.3,131.7,131.4,126.2(2C),113.2(2C),110.0,108.6,107.2(2C),101.6,71.4,66.9,56.4(2C),47.5(2C),45.6,43.5,33.0,31.5.HRMS(ESI):590.2148for[M+H]+(calculated 590.2067for C31H31N3O9).
4.目标产物的合成
称取1.2mmol c1，溶于10mL干燥四氢呋喃中，加SOCl210滴，吡啶1滴，70℃回流1h，旋蒸掉溶剂及过量SOCl2，密封备用；
称取1mmol 4β-N-[(4-硝基苯基)哌嗪]-4′-去甲基表鬼臼毒素和4mmol三乙胺加入到30mL干燥四氢呋喃中；在-20℃的乙醇浴中将事先准备的酰氯滴加到上述四氢呋喃中，滴加时间不少于5min，剧烈搅拌1h，室温下反应2-3h；抽滤，滤液减压浓缩，残留物溶于二氯甲烷，分别用稀醋酸溶液，稀碳酸钠溶液以及饱和氯化钠溶液洗涤。合并有机层用无水NaSO4干燥，然后过滤，滤液减压浓缩，得到的粗品经硅胶柱层析纯化，以石油醚/乙酸乙酯/乙腈(300/100/1)为洗脱剂，可得目标化合物，以下为得到的几个化合物及其表征数据。
d1化合物：2-(3-甲基-2-硝基苯氧基)乙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d1化合物表征：
黄色固体；产率:25％；m.p.:148-150℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.06(d,J＝9.2Hz,2H),7.49(t,J＝8.0Hz,1H),7.43(s,1H),7.1(d,J＝8.4Hz,1H),7.06(d,J＝9.2Hz,1H),7.02(d,J＝9.2Hz,2H),6.58(s,1H),6.38(s,2H),6.01(s,2H),5.32(s,2H),4.63(d,J＝7.2Hz,1H),4.14(dd,J1＝16.0Hz,J2＝12.0Hz,3H),3.65(s,6H),3.51-3.36(m,4H),3.18(dd,J1＝12.0Hz,J2＝4.0Hz,1H),2.63-2.51(m,5H),2.37(s,3H)；
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ175.0,166.9,155.6,153.8,151.3,147.7(2C),147.4,144.3,140.6,137.4(2C),132.4,131.5,127.7(2C),126.3,125.9,117.3,113.2(2C),112.7,111.8,110.0,109.6,107.9(2C),107.3,101.4,71.3,66.6,66.0,56.5(2C),47.5(2C),45.1,43.8,33.4,19.4；
MS(ESI):783.2536for[M+H]+(calculated 783.7597forC40H38N4O13)。
d2化合物：2-(4-甲基-2-硝基苯氧基)乙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d 2化合物表征：
黄色固体；产率:30％；m.p.:151-153℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.07(d,J＝9.2Hz,2H),7.72(s,1H),7.51(d,J＝8.4Hz,1H),7.42(s,1H),7.20(d,J＝8.4Hz,1H),7.04(d,J＝9.2Hz,2H),6.57(s,1H),6.38(s,2H),6.01(s,2H),5.30(s,2H),4.59(d,J＝7.2Hz,1H),4.14(dd,J1＝16.0Hz,J2＝12.0Hz,3H),3.65(s,6H),3.51-3.35(m,4H),3.18(dd,J1＝12.0Hz,J2＝4.0Hz,1H),2.63-2.50(m,5H),2.31(s,3H)；
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ174.8,166.8,155.4,153.7,151.1,147.7(2C),147.2,144.4,140.6,137.4(2C),132.6,131.8,127.7(2C),126.3,126.1,117.3,113.2(2C),112.7,112.1,110.0,109.8,107.9(2C),107.3,101.6,71.5,66.8,66.2,56.5(2C),47.5(2C),45.2,43.8,33.2,18.9；
MS(ESI):783.2562for[M+H]+(calculated 783.7597for C40H38N4O13).。
d3化合物：2-(5-甲基-2-硝基苯氧基)乙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯(d3)，
d3化合物表征：
黄色固体；产率:28％；m.p.:159-161℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.06(d,J＝9.2Hz,2H),7.82(d,J＝8.4Hz,1H),7.42(s,1H),7.12(s,1H),7.04(d,J＝9.2Hz,2H),6.99(d,J＝8.0Hz,1H),6.57(s,1H),6.39(s,2H),6.01(s,2H),5.33(s,2H),4.59(d,J＝7.2Hz,1H),4.14(dd,J1＝16.0Hz,J2＝12.0Hz,3H),3.66(s,6H),3.51-3.34(m,4H),3.18(dd,J1＝12.0Hz,J2＝4.0Hz,1H),2.62-2.50(m,5H),2.35(s,3H)；
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ174.7,166.8,155.2,153.6,151.1,147.7(2C),147.2,144.3,140.6,137.3(2C),132.6,131.6,127.7(2C),126.5,126.3,117.1,113.2(2C),112.7,112.1,110.0,109.2,107.9(2C),107.1,101.2,71.4,66.8,66.1,56.5(2C),47.5(2C),45.1,43.7,33.4,21.1；
MS(ESI):783.2472for[M+H]+(calculated 783.7597for C40H38N4O13).。
d4化合物：2-(3-甲氧基-2-硝基苯氧基)乙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d4化合物表征：
黄色固体；产率:38％；m.p.:170-172℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.07(d,J＝9.2Hz,2H),7.46(s,1H),7.43(s,1H),7.28(d,J＝8.0Hz,2H),7.04(d,J＝8.0Hz,2H),6.58(s,1H),6.39(s,2H),6.01(s,2H),5.25(s,2H),4.58(d,J＝4.0Hz,1H),4.14(dd,J1＝16.0Hz,J2＝12.0Hz,3H),3.79(s,3H),3.64(s,6H),3.51-3.35(m,4H),3.18(dd,J1＝12.0Hz,J2＝4.0Hz,1H),2.63-2.51(m,5H)；
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ174.7,166.9,155.2,153.6,151.1,147.7(2C),147.2,144.4,140.6,140.4,137.4(2C),132.6,131.8,127.7(2C),126.4,126.1,117.3,113.2(2C),112.7,110.0,109.2,107.9(2C),107.3,101.6,71.5,66.8,66.2,56.5(2C),47.5(2C),45.2,43.8,33.2,18.9；
MS(ESI):799.2507for[M+H]+(calculated 799.7582for C40H38N4O14).。
d5化合物：2-(4-甲氧基-2-硝基苯氧基)乙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d5化合物表征：
黄色固体；产率:33％；m.p.:171-173℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.06(d,J＝9.2Hz,2H),7.47(s,1H),7.42(s,1H),7.28(d,J＝8.0Hz,2H),7.04(d,J＝8.0Hz,2H),6.57(s,1H),6.38(s,2H),6.01(s,2H),5.25(s,2H),4.59(d,J＝4.0Hz,1H),4.14(dd,J1＝16.0Hz,J2＝12.0Hz,3H),3.79(s,3H),3.64(s,6H),3.51-3.35(m,4H),3.18(dd,J1＝12.0Hz,J2＝4.0Hz,1H),2.63-2.51(m,5H)；
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ174.8,166.8,155.4,153.7,151.1,147.7(2C),147.2,144.4,140.6,140.4,137.4(2C),132.6,131.8,127.7(2C),126.4,126.1,117.3,113.2(2C),112.7,110.0,109.2,107.9(2C),107.3,101.6,71.5,66.8,66.2,56.5(2C),47.5(2C),45.2,43.8,33.2,18.9；
MS(ESI):799.2507for[M+H]+(calculated 799.7582for C40H38N4O14).。
d6化合物：2-(5-甲氧基-2-硝基苯氧基)乙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯：
d6化合物表征：
黄色固体；产率:37％；m.p.:165-167℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.02(d,J＝8.0Hz,2H),7.94(d,J＝8.0Hz,1H),7.38(s,1H),7.00(d,J＝8.0Hz,2H),6.73(d,J＝9.2Hz,2H),6.53(s,1H),6.35(s,2H),5.97(s,2H),5.33(s,2H),4.58(d,J＝4.0Hz,1H),4.09(dd,J1＝8.0Hz,J2＝4.0Hz,3H),3.85(s,3H),3.60(s,6H),3.47-3.31(m,4H),3.14(dd,J1＝12.0Hz,J2＝4.0Hz,1H),2.61-2.46(m,5H)；
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ174.7,166.8,155.3,153.6,151.1,147.7(2C),147.2,144.3,140.6,140.3,137.3(2C),132.6,131.7,127.7(2C),126.5,126.2,117.2,113.2(2C),112.7,110.1,109.2,107.9(2C),107.1,101.4,71.4,66.8,66.1,56.5(2C),47.5(2C),45.1,43.7,33.4,19.1；
MS(ESI):799.2469for[M+H]+(calculated 799.7582for C40H38N4O14).。
d7化合物：2-(3-氟-2-硝基苯氧基)乙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯,
d7化合物表征：
红色固体；产率:25％；m.p.:240-243℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.04(d,J＝9.2Hz,2H),7.89(dd,J1＝8.0Hz,J2＝4.0Hz,1H),7.66-7.62(m,1H),7.41(s,1H),7.36(dd,J1＝12.0Hz,J2＝4.0Hz,1H),7.02(d,J＝9.2Hz,2H),6.55(s,1H),6.37(s,2H),5.99(s,2H),5.32(s,2H),4.57(d,J＝4.4Hz,1H),4.12(dd,J1＝16.0Hz,J2＝8.0Hz,3H),3.63(s,6H),3.49-3.35(m,4H),3.16(dd,J1＝12.0Hz,J2＝4.0Hz,1H),2.62-2.49(m,5H)；
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ174.7,166.6,157.8,154.3,153.6,151.2,147.3(2C),145.7,140.0,137.4(2C),132.6,130.2,126.3(2C),122.2,121.2,117.3,113.1(2C),112.6,112.5,110.0,109.3,107.2(2C),101.8,70.5,69.2,66.2,65.3,56.7(2C),47.4(2C),45.7,44.1,33.3；
MS(ESI):787.2260for[M+H]+(calculated 787.7220for C39H35FN4O13).。
d8化合物：2-(4-氟-2-硝基苯氧基)乙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯()，
d8化合物表征：
红色固体；产率:28％；m.p.:235-237℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.05(d,J＝8.0Hz,2H),7.68(dd,J1＝16.0Hz,J2＝8.0Hz,1H),7.41(s,1H),7.19(dd,J1＝24.0Hz,J2＝12.0Hz,2H),7.02(d,J＝9.2Hz,2H),6.56(s,1H),6.37(s,2H),5.99(s,2H),5.38(s,2H),4.57(d,J＝4.4Hz,1H),4.12(dd,J1＝16.0Hz,J2＝8.0Hz,3H),3.64(s,6H),3.62-3.45(m,4H),3.16(dd,J1＝12.0Hz,J2＝4.0Hz,1H),2.62-2.49(m,5H)；
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ174.7,166.6,156.9,155.4,154.5,151.0,147.7(2C),147.2,140.1,137.4(2C),132.6,131.8,126.2(2C),121.4,121.2,117.4,113.2(2C),112.8,112.6,110.0,107.9,107.3(2C),101.6,71.5,66.8,66.2,65.5,56.4(2C),47.5(2C),45.2,43.8,33.2；MS(ESI):787.2280for[M+H]+(calculated 787.7220forC39H35FN4O13).。
d9化合物：2-(5-氟-2-硝基苯氧基)乙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d9化合物表征：
红色固体；产率:34％；m.p.:242-244℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.02(d,J＝8.0Hz,2H),7.76(dd,J1＝16.0Hz,J2＝8.0Hz,1H),7.39(s,1H),7.19(dd,J1＝24.0Hz,J2＝12.0Hz,2H),7.02(d,J＝9.2Hz,2H),6.53(s,1H),6.35(s,2H),5.97(s,2H),5.39(s,2H),4.58(d,J＝4.4Hz,1H),4.12(dd,J1＝16.0Hz,J2＝8.0Hz,3H),3.61(s,6H),3.48-3.29(m,4H),3.16(dd,J1＝12.0Hz,J2＝4.0Hz,1H),2.62-2.49(m,5H)；
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ174.6,167.8,158.1,157.2,154.9,151.3,147.3(2C),147.2,140.2,137.4(2C),131.6,130.8,126.1(2C),122.7,121.9,115.3,113.2(2C),112.7,112.2,110.5,109.2,107.1(2C),101.8,70.5,68.9,66.6,65.3,56.7(2C),47.5(2C),45.5,43.9,31.9；MS(ESI):787.2286for[M+H]+(calculated 787.7220forC39H35FN4O13).。
d10化合物：2-(3-溴-2-硝基苯氧基)乙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d10化合物表征：
棕色固体；产率:50％；m.p.:158-160℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.15(s,1H),8.05(d,J＝8.0Hz,2H),7.92(d,J＝8.0Hz,1H),7.43(s,1H),7.28(d,J＝12.0Hz,1H),7.03(d,J＝12.0Hz,2H),6.55(s,1H),6.37(s,2H),6.00(s,2H),5.36(s,2H),4.56(d,J＝4.0Hz,1H),4.12(dd,J1＝16.0Hz,J2＝8.0Hz,3H),3.64(s,6H),3.50-3.33(m,4H),3.17(dd,J1＝16.0Hz,J2＝4.0Hz,1H),2.62-2.49(m,5H)；
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ174.7,166.5,155.3,151.0,149.8,147.8(2C),147.2,140.9,140.5,137.4(2C),136.9,132.6,131.8,127.7(2C),126.3,126.1,117.8,113.2(2C),112.7,110.0,109.2,107.9(2C),107.3,101.6,71.4,66.8,65.9,56.4(2C),47.5(2C),45.2,43.8,33.2；
MS(ESI):847.1464for[M+H]+(calculated 847.1383for C39H35BrN4O13).。
d11化合物：2-(4-溴-2-硝基苯氧基)乙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯,
d11化合物表征：
棕色固体；产率:41％；m.p.:168-169℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.14(s,1H),8.05(d,J＝8.0Hz,2H),7.91(d,J＝8.0Hz,1H),7.41(s,1H),7.28(d,J＝12.0Hz,1H),7.03(d,J＝12.0Hz,2H),6.55(s,1H),6.37(s,2H),6.00(s,2H),5.36(s,2H),4.57(d,J＝4.0Hz,1H),4.12(dd,J1＝16.0Hz,J2＝8.0Hz,3H),3.64(s,6H),3.50-3.33(m,4H),3.17(dd,J1＝16.0Hz,J2＝4.0Hz,1H),2.62-2.49(m,5H)；
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ174.7,166.4,155.4,151.0,149.7,147.7(2C),147.2,140.9,140.5,137.4(2C),136.9,132.6,131.8,127.7(2C),126.3,126.1,117.8,113.2(2C),112.7,110.0,109.2,107.9(2C),107.3,101.6,71.4,66.8,65.9,56.4(2C),47.5(2C),45.2,43.8,33.2；
MS(ESI):847.1464for[M+H]+(calculated 847.1383for C39H35BrN4O13).。
d12化合物：2-(5-溴-2-硝基苯氧基)乙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯,
d12化合物表征：
棕色固体；产率:37％；m.p.:143-144℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.05(d,J＝8.0Hz,2H),7.87(d,J＝8.4Hz,1H),7.54(s,1H),7.40(d,J＝8.0Hz,2H),7.02(d,J＝8.0Hz,2H),6.55(s,1H),6.38(s,2H),5.99(s,2H),5.45(s,2H),4.57(d,J＝4.0Hz,1H),4.12(dd,J1＝16.0Hz,J2＝8.0Hz,3H),3.66(s,6H),3.49-3.37(m,4H),3.17(dd,J1＝16.0Hz,J2＝4.0Hz,1H),2.62-2.49(m,5H)；
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ174.6,166.3,155.2,151.0,149.6,147.7(2C),147.4,140.7,140.1,137.5(2C),136.4,132.5,131.8,127.6(2C),126.3,126.1,116.9,113.2(2C),112.7,110.0,109.1,107.9(2C),107.3,101.6,71.3,66.8,65.9,56.3(2C),47.5(2C),45.1,43.7,32.9；
MS(ESI):847.1489for[M+H]+(calculated 847.1383for C39H35BrN4O13).。
d13化合物：2-(3-氯-2-硝基苯氧基)乙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d13化合物表征：
浅灰色固体；产率:44％；m.p.:239-241℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.08(d,J＝9.2Hz,2H),7.96(d,J＝8.8Hz,1H),7.41(d,J＝3.2Hz,2H),7.38(d,J＝8.8Hz,1H),7.04(d,J＝9.2Hz,2H),6.57(s,1H),6.39(s,2H),6.00(s,2H),5.46(s,2H),4.59(d,J＝4.4Hz,1H),4.14(dd,J1＝16.0Hz,J2＝12.0Hz,3H),3.66(s,6H),3.52-3.36(m,4H),3.18(dd,J1＝12.0Hz,J2＝4.0Hz,1H),2.64-2.51(m,5H)；
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ174.9,166.1,155.7,151.2,151.0,147.7(2C),147.2,140.6,138.9,137.4(2C),132.6,131.8,129.1,127.1(2C),126.2,126.1,122.1,116.2,113.2(2C),110.0,109.1,107.9(2C),107.0,101.6,71.5,66.8,65.9,56.4(2C),47.5(2C),45.2,43.8,33.2；
[M+H]+(calculated 803.1897for C39H35ClN4O13).。
d14化合物：2-(4-氯-2-硝基苯氧基)乙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d14化合物表征：
浅灰色固体；产率:48％；m.p.:243-245℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.07(d,J＝9.2Hz,2H),7.95(d,J＝8.8Hz,1H),7.43(d,J＝3.2Hz,2H),7.39(d,J＝8.8Hz,1H),7.04(d,J＝9.2Hz,2H),6.57(s,1H),6.38(s,2H),6.00(s,2H),5.46(s,2H),4.58(d,J＝4.4Hz,1H),4.14(dd,J1＝16.0Hz,J2＝12.0Hz,3H),3.66(s,6H),3.52-3.36(m,4H),3.18(dd,J1＝12.0Hz,J2＝4.0Hz,1H),2.65-2.51(m,5H)；
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ174.8,166.3,155.9,151.2,151.0,147.7(2C),147.2,140.6,138.9,137.4(2C),132.6,131.8,129.1,127.1(2C),126.2,126.1,122.1,116.2,113.2(2C),110.0,109.1,107.9(2C),107.0,101.6,71.5,66.8,65.9,56.4(2C),47.5(2C),45.2,43.8,33.2；
[M+H]+(calculated 803.1897for C39H35ClN4O13).。
d15化合物：2-(5-氯-2-硝基苯氧基)乙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d15化合物表征：
浅灰色固体；产率:42％；m.p.:241-243℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.07(d,J＝9.2Hz,2H),7.97(d,J＝8.8Hz,1H),7.43(d,J＝3.2Hz,2H),7.38(d,J＝8.8Hz,1H),7.04(d,J＝9.2Hz,2H),6.57(s,1H),6.39(s,2H),6.01(s,2H),5.46(s,2H),4.59(d,J＝4.4Hz,1H),4.14(dd,J1＝16.0Hz,J2＝12.0Hz,3H),3.66(s,6H),3.52-3.36(m,4H),3.18(dd,J1＝12.0Hz,J2＝4.0Hz,1H),2.63-2.50(m,5H)；
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ174.7,166.3,155.5,151.3,151.0,147.7(2C),147.2,140.5,138.9,137.4(2C),132.6,131.8,129.1,127.1(2C),126.2,126.1,122.1,116.2,113.2(2C),110.0,109.1,107.9(2C),107.3,101.6,71.5,66.8,65.9,56.4(2C),47.5(2C),45.2,43.8,33.2；
[M+H]+(calculated 803.1897for C39H35ClN4O13).。
d16化合物：2-(2-硝基苯氧基)乙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d16化合物表征：
淡黄色固体；产率:47％；m.p.:146-147℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.06(d,J＝8.0Hz,1H),7.49(d,J＝8.0Hz,2H),7.70(t,J＝8.0Hz,1H),7.42(s,1H),7.31(d,J＝8.0Hz,1H),7.18(t,J＝8.0Hz,1H),7.04(d,J＝8.0Hz,2H),6.57(s,1H),6.38(s,2H),6.01(s,2H),5.34(s,2H),4.59(d,J＝4.0Hz,1H),4.13(dd,J1＝12.0Hz,J2＝8.0Hz,3H),3.65(s,6H),3.51-3.35(m,4H),3.18(dd,J1＝12.0Hz,J2＝4.0Hz,1H),2.63-2.50(m,5H)；
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ174.8,166.6,155.4,151.1,150.4,147.7(2C),147.2,140.4,140.3,137.4(2C),134.5,132.6,131.8,126.3,126.1(2C),125.5,122.1,115.6,113.2(2C),110.0,107.9,107.3(2C),101.6,73.3,71.9,71.5,66.8,56.4(2C),47.5(2C),45.2,43.8,33.1；MS(ESI):769.2347for[M+H]+(calculated 769.2287forC39H36N4O13).。
d17化合物：2-(2-硝基苯氧基)丙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d17化合物表征：
黄色固体；产率:52％；m.p.:188-190℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.04(d,J＝4.0Hz,2H),7.85(d,J＝8.0Hz,1H),7.66(t,J＝4.0Hz,1H),7.38(s,1H),7.24(d,J＝8.0Hz,1H),7.14(t,J＝8.0Hz,1H),7.01(d,J＝4.0Hz,2H),6.53(s,1H),6.33(s,2H),5.96(s,2H),5.46(dd,J1＝12.0Hz,J2＝4.0Hz,1H),4.54(d,J＝4.0Hz,1H),4.09(dd,J1＝16.0Hz,J2＝8.0Hz,3H),3.58(s,6H),3.47-3.31(m,4H),3.13(dd,J1＝12.0Hz,J2＝4.0Hz,1H),2.58-2.46(m,5H),1.63(d,J＝8.0Hz,3H)；
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ174.7,169.2,155.4,151.1,150.1,147.7(2C),147.2,140.5,140.1,137.4(2C),134.5,132.6,131.8,126.4,126.1(2C),125.5,122.1,116.1,113.2(2C),110.0,107.8,107.3(2C),101.6,73.3,71.9,71.5,66.8,56.4(2C),47.5(2C),45.2,43.8,33.1,19.8；
MS(ESI):783.2518for[M+H]+(calculated 783.7594for C40H38N4O13).。
d18化合物：2-甲基-2-(2-硝基苯氧基)丙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d18化合物表征：
淡黄色固体；产率:39％；m.p.:197-199℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.06(d,J＝8.0Hz,2H),7.98(d,J＝8.0Hz,1H),7.66(t,J＝4.0Hz,1H),7.42(s,1H),7.24(d,J＝8.0Hz,1H),7.18(t,J＝4.0Hz,1H),7.01(d,J＝4.0Hz,2H),6.57(s,1H),6.39(s,2H),6.01(s,2H),4.58(d,J＝4.0Hz,1H),4.12(dd,J1＝8.0Hz,J2＝4.0Hz,3H),3.64(s,6H),3.51-3.34(m,4H),3.18(dd,J1＝12.0Hz,J2＝4.0Hz,1H),2.62-2.49(m,5H),1.98(s,6H)；
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ174.7,171.1,155.4,151.1,147.7(2C),147.5,147.2,142.9,140.5,137.4(2C),133.7,132.5,131.8,125.6,126.1(2C),126.3,125.3,122.9,120.0,113.2(2C),110.0,107.8,107.3(2C),101.7,80.9,71.5,66.8,56.5(2C),47.5(2C),45.3,43.8,33.1,25.4,25.2；
MS(ESI):797.2677for[M+H]+(calculated 797.7865for C41H40N4O13).。
d19化合物：2-(2-硝基苯氧基)丁酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯(()：
d19化合物表征：
棕色固体；产率:30％；m.p.:204-207℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.04(d,J＝4.0Hz,2H),7.85(d,J＝8.0Hz,1H),7.66(t,J＝4.0Hz,1H),7.38(s,1H),7.24(d,J＝8.0Hz,1H),7.14(t,J＝8.0Hz,1H),7.01(d,J＝4.0Hz,2H),6.53(s,1H),6.33(s,2H),5.96(s,2H),5.46(t,J＝4.0Hz,1H),4.54(d,J＝4.0Hz,1H),4.09(dd,J1＝16.0Hz,J2＝8.0Hz,3H),3.58(s,6H),3.47-3.31(m,4H),3.13(dd,J1＝12.0Hz,J2＝4.0Hz,1H),2.58-2.46(m,5H),1.94-1.80(m,2H),1.47(t,J＝8.0Hz,3H)；
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ174.9,171.5,155.5,151.3,147.7(2C),147.5,147.2,142.8,140.7,137.4(2C),133.8,132.5,131.8,125.8,126.1(2C),126.4,125.3,122.9,120.2,113.2(2C),110.1,107.9,107.3(2C),101.7,80.7,71.4,66.7,56.5(2C),47.5(2C),45.2,43.7,33.2,23.6,15.7；
MS(ESI):797.2673for[M+H]+(calculated 797.7865for C41H40N4O13).。
d20化合物：2-甲基-2-(3-甲基-2-硝基苯氧基)丙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d20化合物表征：
黄色固体；产率:39％；m.p.:120-122℃；1H N d5化合物表征：MR(400MHz,DMSO-d6,TMS,ppm):δ8.08(d,J＝9.2Hz,2H),7.73(s,1H),7.51(d,J＝8.0Hz,1H),7.43(s,1H),7.20(d,J＝8.0Hz,1H),7.03(d,J＝12.0Hz,2H),6.57(s,1H),6.39(s,2H),6.01(s,2H),4.59(d,J＝4.0Hz,1H),4.14(dd,J1＝8.0Hz,J2＝4.0Hz,3H),3.65(s,6H),3.51-3.35(m,4H),3.18(dd,J1＝12.0Hz,J2＝4.0Hz,1H),2.63-2.49(m,5H),2.30(s,3H),1.69(s,6H)；
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ176.3,174.2,158.6,150.7,147.6(2C),147.3,147.1,142.5,141.2,137.5(2C),133.2,132.3,130.8,125.6,126.1(2C),126.4,125.8,122.3,121.0,113.2(2C),110.1,107.8,107.3(2C),101.8,82.9,69.5,65.8,56.8(2C),47.5(2C),45.7,44.2,33.2,25.4,25.2,21.3；
MS(ESI):811.2916for[M+H]+(calculated 811.8137for C42H42N4O13).。
d21化合物：2-甲基-2-(4-甲基-2-硝基苯氧基)丙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d21化合物表征：
黄色固体；产率:37％；m.p.:124-126℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.07(d,J＝9.2Hz,2H),7.72(s,1H),7.50(d,J＝8.0Hz,1H),7.43(s,1H),7.20(d,J＝8.0Hz,1H),7.03(d,J＝12.0Hz,2H),6.57(s,1H),6.39(s,2H),6.01(s,2H),4.59(d,J＝4.0Hz,1H),4.14(dd,J1＝8.0Hz,J2＝4.0Hz,3H),3.65(s,6H),3.51-3.35(m,4H),3.18(dd,J1＝12.0Hz,J2＝4.0Hz,1H),2.63-2.49(m,5H),2.30(s,3H),1.69(s,6H)；
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ176.2,174.1,158.4,150.6,147.6(2C),147.3,147.1,142.5,141.2,137.5(2C),133.2,132.3,130.8,125.6,126.1(2C),126.4,125.8,122.3,121.0,113.2(2C),110.1,107.8,107.3(2C),101.8,82.9,69.5,65.8,56.8(2C),47.5(2C),45.7,44.2,33.2,25.4,25.2,21.3；
MS(ESI):811.2916for[M+H]+(calculated 811.8137for C42H42N4O13).。
d22化合物：2-甲基-2-(5-甲基-2-硝基苯氧基)丙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d22化合物表征：
黄色固体；产率:35％；m.p.:137-139℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.06(d,J＝8.0Hz,2H),7.79(d,J＝8.0Hz,1H),7.43(s,1H),7.27(s,1H),7.18(d,J＝8.0Hz,1H),7.01(d,J＝12.0Hz,2H),6.57(s,1H),6.38(s,2H),6.01(s,2H),4.60(d,J＝4.0Hz,1H),4.14(dd,J1＝8.0Hz,J2＝4.0Hz,3H),3.67(s,6H),3.51-3.35(m,4H),3.18(dd,J1＝12.0Hz,J2＝4.0Hz,1H),2.62-2.50(m,5H),2.27(s,3H),1.67(s,6H)
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ174.7,171.2,155.4,151.1,147.6(2C),147.3,147.1,144.9,140.5,137.5(2C),132.5,132.2,130.0,126.7,126.2(2C),126.1,125.4,123.6,120.6,115.2(2C),113.2,107.9,107.3(2C),101.7,81.3,71.5,66.8,56.5(2C),47.5(2C),45.2,43.7,33.1,25.4,21.9,19.1；
MS(ESI):811.4158for[M+H]+(calculated 811.8137for C42H42N4O13).。
d23化合物：2-甲基-2-(3-甲基-2-硝基苯氧基)丙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d23化合物表征：
黄色固体；产率:42％；m.p.:137-139℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.09–7.96(m,3H),7.03–6.90(m,2H),6.90–6.76(m,3H),6.70(s,1H),6.50–6.46(m,2H),5.92–5.88(m,2H),4.76(s,1H),4.37(s,1H),4.12(s,1H),3.88(s,1H),3.82–3.78(m,3H),3.77–3.73(m,6H),3.65–3.60(m,4H),3.51(s,1H),3.25(s,1H),2.91–2.87(m,2H),2.83–2.79(m,2H),1.82–1.78(m,6H).
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ176.26(s),173.80(s),163.29(s),158.69(s),154.41(s),153.48–153.09(m),147.34(d,J＝1.5Hz),139.73(s),137.55(s),133.23(s),130.98(s),129.78(s),129.48(s),127.85(s),126.54–126.33(m),112.64–112.24(m),110.56(s),110.01(s),108.73–108.52(m),107.89(s),106.19(s),101.78(s),82.99(s),69.29(s),65.32(s),56.89–56.58(m),56.04(s),52.02–51.63(m),50.51–50.20(m),45.72(s),43.76(s),40.52(s),23.92–23.60(m).
MS(ESI):827.2758for[M+H]+(calculated 827.8137for C42H42N4O14).。
d24化合物：2-甲基-2-(4-甲基-2-硝基苯氧基)丙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d24化合物表征：
黄色固体；产率:35％；m.p.:137-139℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.09–7.96(m,2H),7.69(s,1H),7.21(s,1H),7.12–6.94(m,3H),6.90(s,1H),6.79(s,1H),6.50–6.46(m,2H),5.92–5.88(m,2H),4.76(s,1H),4.37(s,1H),4.12(s,1H),3.88(s,1H),3.84–3.80(m,3H),3.76–3.72(m,6H),3.71–3.67(m,2H),3.55–3.51(m,2H),3.37(s,1H),3.26(s,1H),2.86–2.82(m,2H),2.76–2.72(m,2H),1.82–1.78(m,6H).
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ176.26(s),173.80(s),158.69(s),156.10(s),153.48–153.09(m),147.34(d,J＝1.5Hz),144.04(s),141.40(s),139.73(s),137.55(s),130.98(s),129.78(s),129.48(s),126.54–126.33(m),121.15(s),116.91(s),112.73(s),112.63–112.24(m),110.56(s),110.01(s),108.73–108.52(m),101.78(s),82.99(s),69.29(s),65.32(s),56.89–56.58(m),56.04(s),52.02–51.63(m),50.51–50.20(m),45.72(s),43.76(s),40.52(s),23.92–23.60(m).
MS(ESI):827.3758for[M+H]+(calculated 827.8137for C42H42N4O14).。
d25化合物：2-甲基-2-(5-甲基-2-硝基苯氧基)丙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d25化合物表征：
黄色固体；产率:39％；m.p.:137-139℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.08–7.94(m,2H),7.56(s,1H),6.99–6.87(m,3H),6.86–6.69(m,3H),6.62–6.58(m,2H),5.92–5.88(m,2H),4.76(s,1H),4.37(s,1H),4.12(s,1H),3.88(s,1H),3.84–3.80(m,3H),3.79–3.75(m,6H),3.66–3.60(m,4H),3.54(s,1H),3.26(s,1H),2.92–2.88(m,2H),2.84–2.80(m,2H),1.82–1.78(m,6H).
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ176.26(s),173.80(s),158.69(s),155.20(s),154.33(s),153.48–153.09(m),147.34(d,J＝1.5Hz),139.73(s),137.55(s),132.52(s),130.98(s),129.97(s),129.78(s),129.48(s),126.54–126.33(m),114.60(s),112.64–112.24(m),110.53(d,J＝5.9Hz),110.01(s),108.73–108.52(m),101.78(s),82.99(s),69.29(s),65.32(s),56.89–56.58(m),52.02–51.63(m),50.51–50.20(m),45.72(s),43.76(s),40.52(s),23.92–23.60(m).
MS(ESI):827.2858for[M+H]+(calculated 827.8237for C42H42N4O14).。
d26化合物：2-甲基-2-(3-氟-2-硝基苯氧基)丙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d26化合物表征：
红色固体；产率:52％；m.p.:128-130℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.08–7.94(m,2H),7.56(s,1H),6.98–6.87(m,3H),6.82(d,J＝4.0Hz,2H),6.74(s,1H),6.71–6.67(m,2H),5.92–5.88(m,2H),4.76(s,1H),4.37(s,1H),4.12(s,1H),3.99–3.63(m,9H),3.81–3.63(m,2H),3.68–3.64(m,2H),3.63–3.59(m,2H),3.08(s,1H),2.92(t,J＝4.1Hz,3H),2.72–2.68(m,2H),1.85–1.81(m,6H).
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ176.26(s),173.80(s),158.69(s),153.48–153.09(m),151.19(s),147.34(d,J＝1.5Hz),139.73(s),137.55(s),134.20(s),130.98(s),130.38(d,J＝150.7Hz),129.87(dd,J＝126.8,89.5Hz),126.54–126.33(m),115.26(s),112.40(t,J＝8.3Hz),110.56(s),110.01(s),108.73–108.52(m),101.78(s),82.99(s),69.29(s),65.32(s),56.89–56.58(m),52.02–51.63(m),50.51–50.20(m),45.72(s),43.76(s),40.52(s),23.92–23.60(m).
MS(ESI):815.2578for[M+H]+(calculated 815.8237for C41H39FN4O13).。
d27化合物：2-甲基-2-(4-氟-2-硝基苯氧基)丙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
红色固体；产率:40％；m.p.:119-121℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.08–7.94(m,2H),7.83(s,1H),7.34(s,1H),7.06(s,1H),6.99–6.84(m,2H),6.81(s,1H),6.76–6.70(m,3H),5.92–5.88(m,2H),4.76(s,1H),4.37(s,1H),4.12(s,1H),3.98–3.74(m,7H),3.68–3.64(m,2H),3.63–3.59(m,2H),3.07(s,1H),2.90(t,J＝1.5Hz,3H),2.72–2.68(m,2H),1.83–1.79(m,6H).
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ176.26(s),173.80(s),158.90(s),158.27(d,J＝104.3Hz),153.48–153.09(m),148.18(s),147.34(d,J＝1.5Hz),139.73(s),137.55(s),136.81(s),130.98(s),129.78(s),129.48(s),126.54–126.33(m),123.72(s),121.84(s),114.83(s),112.64–112.24(m),110.56(s),110.01(s),108.73–108.52(m),101.78(s),82.99(s),69.29(s),65.32(s),56.89–56.58(m),52.02–51.63(m),50.51–50.20(m),45.72(s),43.76(s),40.52(s),23.92–23.60(m).
MS(ESI):815.2578for[M+H]+(calculated 815.8237for C41H39FN4O13).。
d28化合物：2-甲基-2-(5-氟-2-硝基苯氧基)丙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d28化合物表征：
红色固体；产率:29％；m.p.:132-134℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.13(s,1H),8.08–7.94(m,2H),7.06(s,1H),7.01(s,1H),6.99–6.84(m,2H),6.81(s,1H),6.72(s,1H),6.69–6.65(m,2H),5.92–5.88(m,2H),4.76(s,1H),4.37(s,1H),4.12(s,1H),3.88(s,1H),3.82–3.78(m,6H),3.68–3.64(m,2H),3.63–3.59(m,2H),3.06(s,1H),2.92–2.87(m,3H),2.71–2.67(m,2H),1.86–1.82(m,6H).
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ176.26(s),173.80(s),163.20(s),158.69(s),153.85(s),153.48–153.09(m),147.34(d,J＝1.5Hz),139.73(s),137.55(s),130.98(s),129.78(s),129.57(d,J＝23.2Hz),129.10(s),126.54–126.33(m),112.64–112.24(m),110.56(s),110.01(s),109.74(s),108.92(t,J＝54.4Hz),108.52–107.59(m),101.78(s),82.99(s),69.29(s),65.32(s),56.89–56.58(m),52.02–51.63(m),50.51–50.20(m),45.72(s),43.76(s),40.52(s),23.92–23.60(m).
MS(ESI):815.2578for[M+H]+(calculated 815.8237for C41H39FN4O13).。
d29化合物：2-甲基-2-(3-溴-2-硝基苯氧基)丙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d29化合物表征：
棕色固体；产率:42％；m.p.:159-161℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.08–7.94(m,8H),7.47(s,4H),7.37(s,4H),7.03(s,4H),6.95–6.84(m,8H),6.81(s,4H),6.75–6.70(m,12H),5.92–5.88(m,8H),4.76(s,4H),4.37(s,4H),4.12(s,4H),3.98–3.76(m,27H),3.76–3.75(m,1H),3.68–3.64(m,8H),3.63–3.59(m,8H),3.07(s,4H),2.90(t,J＝1.3Hz,12H),2.72–2.68(m,8H),1.82–1.78(m,24H).
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ176.26(s),173.80(s),158.69(s),153.48–153.09(m),152.48(s),147.34(d,J＝1.5Hz),139.73(s),138.83(s),137.55(s),134.82(s),130.98(s),129.78(s),129.48(s),126.54–126.33(m),125.39(s),121.30(s),120.25(s),112.64–112.24(m),110.56(s),110.01(s),108.73–108.52(m),101.78(s),82.99(s),69.29(s),65.32(s),56.89–56.58(m),52.02–51.63(m),50.51–50.20(m),45.72(s),43.76(s),40.52(s),23.92–23.60(m).
MS(ESI):876.2146for[M+H]+(calculated 876.2067for C41H39BrN4O13).。
d30化合物2-甲基-2-(4-溴-2-硝基苯氧基)丙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d30化合物表征：
棕色固体；产率:35％；m.p.:148-150℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.27(s,1H),8.08–7.94(m,2H),7.78(s,1H),7.04–6.87(m,4H),6.79(s,1H),6.61–6.57(m,2H),5.92–5.88(m,2H),4.76(s,1H),4.37(s,1H),4.12(s,1H),3.88(s,1H),3.79–3.75(m,6H),3.66–3.59(m,4H),3.54(s,1H),3.27(s,1H),2.92–2.88(m,2H),2.84–2.80(m,2H),1.83–1.79(m,6H).
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ176.26(s),173.80(s),158.69(s),153.48–153.09(m),152.36(s),147.34(d,J＝1.5Hz),139.73(s),137.55(s),137.34(s),135.42(s),130.98(s),129.78(s),129.48(s),128.94(s),126.54–126.33(m),122.29(s),117.34(s),112.64–112.24(m),110.56(s),110.01(s),108.73–108.52(m),101.78(s),82.99(s),69.29(s),65.32(s),56.89–56.58(m),52.02–51.63(m),50.51–50.20(m),45.72(s),43.76(s),40.52(s),23.92–23.60(m).
MS(ESI):876.2146for[M+H]+(calculated 876.2067for C41H39BrN4O13).。
d31化合物：2-甲基-2-(5-溴-2-硝基苯氧基)丙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d31化合物表征：
棕色固体；产率:40％；m.p.:156-158℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.07(d,J＝8.0Hz,2H),7.82(d,J＝8.4Hz,1H),7.53(s,1H),7.42(s,1H),7.39(d,J＝8.0Hz,1H),7.02(d,J＝8.0Hz,2H),6.56(s,1H),6.38(s,2H),5.99(s,2H),4.59(d,J＝4.0Hz,1H),4.11(dd,J1＝16.0Hz,J2＝8.0Hz,3H),3.66(s,6H),3.49-3.37(m,4H),3.17(dd,J1＝16.0Hz,J2＝4.0Hz,1H),2.62-2.49(m,5H),1.66(s,6H)；
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ176.2,174.2,158.6,150.1,147.6(2C),147.1,146.8,142.5,139.7,137.6(2C),133.1,132.0,130.5,125.2,126.4(2C),126.1,125.1,121.5,121.1,115.1(2C),111.0,107.6,107.3(2C),101.6,82.8,69.3,65.3,56.8(2C),47.6(2C),45.7,44.1,33.1,24.2,21.8；
MS(ESI):876.2146for[M+H]+(calculated 876.2067for C41H39BrN4O13).。
d32化合物：2-甲基-2-(5-氯-2-硝基苯氧基)丙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d32化合物表征：
浅灰色固体；产率:50％；m.p.:118-120℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.08–7.94(m,2H),7.57(s,1H),7.28(s,1H),7.13(s,1H),6.99–6.87(m,3H),6.79(s,1H),6.61–6.57(m,2H),5.92–5.88(m,2H),4.76(s,1H),4.37(s,1H),4.12(s,1H),3.88(s,1H),3.79–3.75(m,6H),3.66–3.62(m,4H),3.54(s,1H),3.26(s,1H),2.92–2.88(m,2H),2.84–2.80(m,2H),1.81–1.77(m,6H).
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ176.26(s),173.80(s),158.69(s),153.48–153.09(m),150.17(s),147.34(d,J＝1.5Hz),139.73(s),137.55(s),136.11(s),134.45(s),130.98(s),129.78(s),129.48(s),127.80(s),126.54–126.33(m),123.84(s),120.99(s),112.64-112.24(m),110.56(s),110.01(s),108.73–108.52(m),101.78(s),82.99(s),69.29(s),65.32(s),56.89–56.58(m),52.02–51.63(m),50.51–50.20(m),45.72(s),43.76(s),40.52(s),23.92–23.60(m).
MS(ESI):876.2146for[M+H]+(calculated 876.2067for C41H39ClN4O13).。
d33化合物：2-甲基-2-(5-氯-2-硝基苯氧基)丙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d33化合物表征：
浅灰色固体；产率:49％；m.p.:121-123℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.13(s,3H),8.08–7.94(m,6H),7.63(s,3H),7.04(s,3H),6.95–6.87(m,9H),6.78(s,3H),6.62–6.58(m,6H),5.92–5.88(m,6H),4.76(s,3H),4.37(s,3H),4.12(s,3H),3.95–3.79(m,20H),3.79–3.78(m,1H),3.67–3.59(m,12H),3.55(s,2H),3.27(s,3H),2.92–2.88(m,6H),2.84–2.80(m,6H),1.73–1.69(m,18H).
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ176.26(s),173.80(s),158.69(s),153.48–153.09(m),150.48(s),147.34(d,J＝1.5Hz),139.73(s),137.92(s),137.55(s),133.31(s),130.98(s),129.78(s),129.48(s),126.54–126.33(m),125.38(d,J＝6.9Hz),123.71(s),112.64–112.24(m),110.56(s),110.01(s),108.73–108.52(m),101.78(s),82.99(s),69.29(s),65.32(s),56.89–56.58(m),52.02–51.63(m),50.51–50.20(m),45.72(s),43.76(s),40.52(s),23.92–23.60(m).
MS(ESI):876.2146for[M+H]+(calculated 876.2067for C41H39ClN4O13).。
d34化合物：2-甲基-2-(5-氯-2-硝基苯氧基)丙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d34化合物表征：
浅灰色固体；产率:52％；m.p.:136-138℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.08–7.91(m,3H),7.21(s,1H),7.13(s,1H),6.99–6.84(m,2H),6.81(s,1H),6.78–6.70(m,3H),5.92–5.88(m,2H),4.76(s,1H),4.37(s,1H),4.12(s,1H),3.88(s,1H),3.81–3.77(m,6H),3.68–3.64(m,2H),3.63–3.59(m,2H),3.07(s,1H),2.97–2.88(m,3H),2.72–2.68(m,2H),1.83–1.79(m,6H).
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ176.26(s),173.80(s),158.69(s),153.98(s),153.48–153.09(m),147.34(d,J＝1.5Hz),139.74(d,J＝4.1Hz),137.55(s),135.97(s),130.98(s),129.78(s),129.48(s),128.84(s),126.54–126.33(m),123.56(s),120.51(s),112.64–112.24(m),110.56(s),110.01(s),108.73–108.52(m),101.78(s),82.99(s),69.29(s),65.32(s),56.89–56.58(m),52.02–51.63(m),50.51–50.20(m),45.72(s),43.76(s),40.52(s),23.92–23.60(m).
MS(ESI):876.2146for[M+H]+(calculated 876.2067for C41H39ClN4O13).。
d35化合物：2-(3-甲基-2-硝基苯氧基)丙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d35化合物表征：
黄色固体；产率:50％；m.p.:117-119℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.09–7.95(m,2H),7.64(s,1H),7.11(d,J＝1.2Hz,2H),7.03–6.88(m,2H),6.81(s,1H),6.75(s,1H),6.64–6.60(m,2H),5.92–5.88(m,2H),4.76(s,1H),4.56(s,1H),4.37(s,1H),4.12(s,1H),3.88(s,1H),3.79–3.75(m,6H),3.70–3.66(m,2H),3.50–3.46(m,2H),3.03(s,1H),2.93(t,J＝9.0Hz,3H),2.67–2.63(m,2H),2.41–2.37(m,3H),1.75–1.62(m,3H).
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ176.26(s),172.71(s),158.69(s),153.46–153.25(m),151.33(s),147.34(d,J＝1.5Hz),140.07(s),139.73(s),138.06(s),135.80(s),131.49(d,J＝4.1Hz),129.78(s),129.48(s),126.54–126.33(m),125.65(s),117.58(s),112.64–112.24(m),110.56(s),110.01(s),108.38–108.16(m),101.78(s),72.77(s),69.29(s),65.32(s),56.89–56.58(m),52.02–51.63(m),50.51–50.20(m),45.72(s),43.76(s),40.52(s),19.38(s),17.27(s).
MS(ESI):797.2598for[M+H]+(calculated 797.7868for C41H40N4O13).。
d36化合物：2-(4-甲基-2-硝基苯氧基)丙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d36化合物表征：
黄色固体；产率:42％；m.p.:113-115℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.07(d,J＝8.0Hz,2H),7.71(s,1H),7.53(d,J＝8.0Hz,1H),7.42(s,1H),7.15(d,J＝8.0Hz,1H),7.06(d,J＝8.0Hz,2H),6.58(s,1H),6.38(s,2H),6.01(s,2H),5.46(dd,J1＝12.0Hz,J2＝4.0Hz,1H),4.59(d,J＝4.0Hz,1H),4.14(dd,J1＝16.0Hz,J2＝8.0Hz,3H),3.63(s,6H),3.49-3.35(m,4H),3.15(dd,J1＝12.0Hz,J2＝4.0Hz,1H),2.61-2.50(m,5H),2.31(s,3H),1.65(d,J＝8.0Hz,3H)；
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ175.2,169.7,157.4,151.1,148.9,147.6(2C),147.3,139.7,138.4,137.6(2C),133.5,132.6,129.7,126.4,126.3(2C),125.5,122.1,115.9,113.0(2C),110.1,107.8,107.3(2C),101.6,72.7,71.9,69.5,65.8,56.7(2C),47.6(2C),45.7,44.0,32.8,19.5,15.3；
MS(ESI):797.2598for[M+H]+(calculated 797.7868for C41H40N4O13).。
d37化合物：2-(5-甲基-2-硝基苯氧基)丙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d37化合物表征：
黄色固体；产率:28％；m.p.:121-123℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.15–7.95(m,3H),7.11(s,1H),7.07(s,1H),7.02–6.88(m,2H),6.86(s,1H),6.80(s,1H),6.70–6.66(m,2H),5.92–5.88(m,2H),4.76(s,1H),4.62(s,1H),4.37(s,1H),4.12(s,1H),3.88(s,1H),3.80–3.76(m,6H),3.70–3.66(m,2H),3.52–3.48(m,2H),3.03(s,1H),2.77(dt,J＝15.9,8.0Hz,5H),2.30–2.26(m,3H),1.78–1.65(m,3H).
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ176.26(s),172.71(s),158.69(s),153.46–153.25(m),152.38(s),147.34(d,J＝1.5Hz),145.03(s),139.73(s),138.06(s),134.84(s),131.50(s),129.78(s),129.48(s),126.84(s),126.54–126.33(m),124.85(s),118.97(s),112.64–112.24(m),110.56(s),110.01(s),108.38–108.16(m),101.78(s),72.77(s),69.29(s),65.32(s),56.89–56.58(m),52.02–51.63(m),50.51–50.20(m),45.72(s),43.76(s),40.52(s),21.39(s),17.27(s).
MS(ESI):797.2598for[M+H]+(calculated 797.7868for C41H40N4O13).。
d38化合物：2-(3-甲氧基-2-硝基苯氧基)丙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
黄色固体；产率:50％；m.p.:156-158℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.09–7.94(m,2H),7.55(s,1H),6.99–6.85(m,2H),6.83–6.72(m,6H),5.92–5.88(m,2H),4.99(s,1H),4.76(s,1H),4.37(s,1H),4.12(s,1H),3.88(s,1H),3.84–3.78(m,9H),3.67–3.62(m,4H),3.29(s,1H),3.11(s,1H),2.90–2.86(m,2H),2.83–2.79(m,2H),1.75–1.62(m,3H).
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ176.26(s),172.71(s),158.69(s),155.90(s),154.14(s),153.46–153.25(m),147.34(d,J＝1.5Hz),139.73(s),138.06(s),132.58(s),131.50(s),129.78(s),129.48(s),129.05(s),126.54–126.33(m),112.64–112.24(m),111.68(s),110.82(s),110.56(s),110.01(s),108.38–108.16(m),101.78(s),72.77(s),69.29(s),65.32(s),56.89–56.58(m),52.02–51.63(m),50.51–50.20(m),45.72(s),43.76(s),40.52(s),17.27(s).
MS(ESI):813.3543for[M+H]+(calculated 813.7857for C41H40N4O14).。
d39化合物：2-(4-甲氧基-2-硝基苯氧基)丙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d39化合物表征：
黄色固体；产率:38％；m.p.:152-154℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.06(d,J＝8.0Hz,2H),7.49(s,1H),7.43(s,1H),7.25(d,J＝8.0Hz,2H),7.06(d,J＝8.0Hz,2H),6.58(s,1H),6.38(s,2H),6.01(s,2H),5.42(dd,J1＝12.0Hz,J2＝4.0Hz,1H),4.61(d,J＝4.0Hz,1H),4.14(dd,J1＝16.0Hz,J2＝8.0Hz,3H),3.79(s,3H),3.64(s,6H),3.51-3.39(m,4H),3.18(dd,J1＝12.0Hz,J2＝4.0Hz,1H),2.63-2.51(m,5H),1.67(d,J＝8.0Hz,3H)；
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ176.3,172.9,158.7,151.2,147.9,147.3(2C),146.9,139.7,138.3,137.4(2C),133.3,132.5,129.8,126.4,126.2(2C),125.5,122.1,116.9,113.2(2C),110.1,106.8,107.2(2C),101.8,72.7,71.9,69.3,65.3,56.8(2C),56.1,47.6(2C),45.7,44.0,40.5,19.5；
MS(ESI):813.3543for[M+H]+(calculated 813.7857for C41H40N4O14).。
d40化合物：2-(5-甲氧基-2-硝基苯氧基)丙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d40化合物表征：
黄色固体；产率:48％；m.p.:142-144℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.05–8.01(m,3H),7.03–6.93(m,3H),6.89(s,1H),6.79(s,1H),6.75(s,1H),6.70–6.66(m,2H),5.92–5.88(m,2H),4.88(s,1H),4.37(d,J＝3.0Hz,2H),4.12(s,1H),3.88(s,1H),3.84–3.77(m,9H),3.64–3.59(m,4H),3.20(s,1H),2.88(t,J＝5.0Hz,3H),2.82–2.79(m,2H),1.76–1.63(m,3H).
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ176.26(s),172.71(s),164.01(s),158.69(s),154.11(s),153.46–153.25(m),147.34(d,J＝1.5Hz),139.73(s),138.06(s),131.50(s),131.23(s),129.78(s),129.48(s),128.17(s),126.54–126.33(m),112.64–112.24(m),110.56(s),110.01(s),108.53(s),108.38–108.16(m),105.00(s),101.78(s),72.77(s),69.29(s),65.32(s),56.89–56.58(m),56.04(s),52.02–51.63(m),50.51–50.20(m),45.72(s),43.76(s),40.52(s),17.27(s).
MS(ESI):813.3543for[M+H]+(calculated 813.7857for C41H40N4O14).。
d41化合物：2-(3-氟-2-硝基苯氧基)丙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d41化合物表征：
红棕色固体；产率:38％；m.p.:124-126℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.09–7.95(m,2H),7.56(s,1H),7.02–6.89(m,3H),6.85–6.76(m,3H),6.60–6.56(m,2H),5.92–5.88(m,2H),4.99(s,1H),4.76(s,1H),4.37(s,1H),4.12(s,1H),3.88(s,1H),3.81–3.77(m,6H),3.69–3.65(m,2H),3.53–3.49(m,2H),3.01(s,1H),2.89–2.85(m,2H),2.67(t,J＝19.0Hz,3H),1.84–1.71(m,3H).
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ176.26(s),172.71(s),159.83(s),158.69(s),153.46–153.25(m),150.98(s),147.34(d,J＝1.5Hz),139.73(s),138.06(s),134.29(s),131.50(s),129.78(s),129.48(s),128.02(s),126.54–126.33(m),114.15(s),112.84(t,J＝73.0Hz),110.56(s),110.01(s),108.38–108.16(m),101.78(s),72.77(s),69.29(s),65.32(s),56.89–56.58(m),52.02–51.63(m),50.51–50.20(m),45.72(s),43.76(s),40.52(s),17.27(s).
MS(ESI):801.2343for[M+H]+(calculated 801.3347for C40H37FN4O13).。
d42化合物：2-(4-氟-2-硝基苯氧基)丙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d42化合物表征：
红棕色固体；产率:38％；m.p.:131-133℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.09–7.98(m,2H),7.90(s,1H),7.49(s,1H),7.15(s,1H),7.01–6.87(m,2H),6.82(s,1H),6.77(s,1H),6.70–6.66(m,2H),5.92–5.88(m,2H),4.76(s,1H),4.54(s,1H),4.37(s,1H),4.12(s,1H),3.88(s,1H),3.79–3.75(m,6H),3.69–3.65(m,2H),3.53–3.49(m,2H),3.01(s,1H),2.90–2.86(m,2H),2.76(s,1H),2.67–2.63(m,2H),1.77–1.64(m,3H).
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ176.26(s),172.71(s),157.73(d,J＝239.7Hz),153.46–153.25(m),147.31(t,J＝4.8Hz),139.73(s),138.06(s),136.39(s),131.50(s),129.78(s),129.48(s),126.54–126.33(m),121.51(d,J＝3.0Hz),114.07(s),112.64–112.24(m),110.56(s),110.01(s),108.38–108.16(m),101.78(s),72.77(s),69.29(s),65.32(s),56.89–56.58(m),52.02–51.63(m),50.51–50.20(m),45.72(s),43.76(s),40.52(s),17.27(s).
MS(ESI):801.2343for[M+H]+(calculated 801.3347for C40H37FN4O13).。
d43化合物：2-(5-氟-2-硝基苯氧基)丙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯,
d43化合物表征：
红棕色固体；产率:47％；m.p.:140-142℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.11(s,1H),8.08–7.94(m,2H),7.07(s,1H),7.02(s,1H),6.99–6.85(m,2H),6.80(s,1H),6.74–6.68(m,3H),5.92–5.88(m,2H),4.76(s,1H),4.72(s,1H),4.37(s,1H),4.12(s,1H),3.96–3.76(m,7H),3.66–3.59(m,4H),3.24(s,1H),2.94(s,1H),2.89–2.85(m,2H),2.82–2.78(m,2H),1.78–1.65(m,3H).
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ176.26(s),172.71(s),164.57(s),158.69(s),153.92(s),153.46–153.25(m),147.34(d,J＝1.5Hz),139.73(s),138.06(s),131.50(s),130.02(s),129.78(s),129.51(d,J＝8.0Hz),126.54–126.33(m),112.64–112.24(m),110.79(s),110.56(s),110.01(s),108.38–108.16(m),107.50(s),101.78(s),72.77(s),69.29(s),65.32(s),56.89–56.58(m),52.02–51.63(m),50.51–50.20(m),45.72(s),43.76(s),40.52(s),17.27(s).
MS(ESI):801.2343for[M+H]+(calculated 801.3347for C40H37FN4O13).。
d44化合物：2-(3-溴-2-硝基苯氧基)丙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d44化合物表征：
棕色固体；产率:50％；m.p.:114-116℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.09–7.95(m,2H),7.47(s,1H),7.37(s,1H),7.06(s,1H),7.01–6.87(m,2H),6.83(s,1H),6.74(s,1H),6.72–6.68(m,2H),5.92–5.88(m,2H),5.00(s,1H),4.76(s,1H),4.37(s,1H),4.12(s,1H),3.88(s,1H),3.79–3.75(m,6H),3.69–3.65(m,2H),3.59–3.55(m,2H),3.10(s,1H),2.88–2.78(m,5H),1.78–1.65(m,3H).
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ176.26(s),172.71(s),158.69(s),153.46–153.25(m),153.10(s),147.34(d,J＝1.5Hz),139.73(s),139.23(s),138.06(s),136.45(s),131.50(s),129.78(s),129.48(s),126.54–126.33(m),125.22(s),119.22(s),118.99(s),112.64–112.24(m),110.56(s),110.01(s),108.38–108.16(m),101.78(s),72.77(s),69.29(s),65.32(s),56.89–56.58(m),52.02–51.63(m),50.51–50.20(m),45.72(s),43.76(s),40.52(s),17.27(s).
MS(ESI):861.1543for[M+H]+(calculated 861.5587for C40H37BrN4O13).。
d45化合物：2-(4-溴-2-硝基苯氧基)丙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
D45化合物表征：
棕色固体；产率:45％；m.p.:124-126℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.35(s,4H),8.09–7.95(m,8H),7.82(s,4H),7.16(s,4H),6.99–6.85(m,8H),6.79(s,4H),6.71–6.66(m,12H),5.92–5.88(m,8H),4.76(d,J＝2.3Hz,8H),4.37(s,4H),4.12(s,4H),3.95–3.79(m,27H),3.79–3.78(m,1H),3.69–3.65(m,8H),3.61–3.57(m,8H),3.22(s,4H),2.96(s,4H),2.90–2.86(m,8H),2.79–2.75(m,8H),1.78–1.65(m,12H).
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ176.26(s),172.71(s),158.69(s),153.46–153.25(m),152.42(s),147.34(d,J＝1.5Hz),139.73(s),138.00(d,J＝13.3Hz),136.11(s),131.50(s),130.09(s),129.78(s),129.48(s),126.54–126.33(m),120.83(s),117.87(s),112.64–112.24(m),110.56(s),110.01(s),108.38–108.16(m),101.78(s),72.77(s),69.29(s),65.32(s),56.89–56.58(m),52.02–51.63(m),50.51–50.20(m),45.72(s),43.76(s),40.52(s),17.27(s).
MS(ESI):861.1543for[M+H]+(calculated 861.5587for C40H37BrN4O13).。
d46化合物：2-(5-溴-2-硝基苯氧基)丙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d46化合物表征：
棕色固体；产率:52％；m.p.:134-136℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.09–7.89(m,15H),7.54(s,3H),7.46(s,7H),6.99–6.84(m,10H),6.79(d,J＝8.2Hz,10H),6.72–6.68(m,10H),5.92–5.88(m,10H),5.01(s,5H),4.76(s,5H),4.37(s,5H),4.12(s,5H),3.97–3.71(m,36H),3.71(s,1H),3.66–3.59(m,20H),3.25(s,5H),2.94(s,5H),2.89–2.85(m,10H),2.82–2.78(m,10H),1.83–1.71(m,15H).
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ176.26(s),172.71(s),158.69(s),154.48(s),153.46–153.25(m),147.34(d,J＝1.5Hz),139.73(s),138.06(s),135.85(s),131.52(s),131.41(d,J＝22.8Hz),129.78(s),129.48(s),128.52(s),126.54–126.33(m),124.42(s),121.32(s),112.64–112.24(m),110.56(s),110.01(s),108.38–108.16(m),101.78(s),72.77(s),69.29(s),65.32(s),56.89–56.58(m),52.02–51.63(m),50.51–50.20(m),45.72(s),43.76(s),40.52(s),17.27(s).
MS(ESI):861.1543for[M+H]+(calculated 861.5587for C40H37BrN4O13).。
d47化合物：2-(3-氯-2-硝基苯氧基)丙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d47化合物表征：
浅灰色固体；产率:38％；m.p.:157-159℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.09–7.94(m,2H),7.52(s,1H),7.23(s,1H),7.03(s,1H),7.01–6.87(m,2H),6.81(s,1H),6.77(s,1H),6.67–6.63(m,2H),5.92–5.88(m,2H),4.98(s,1H),4.76(s,1H),4.37(s,1H),4.12(s,1H),3.88(s,1H),3.77–3.73(m,6H),3.68–3.64(m,2H),3.53–3.49(m,2H),2.98(s,1H),2.89–2.85(m,2H),2.66(t,J＝12.0Hz,3H),1.77–1.65(m,3H).
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ176.26(s),172.71(s),158.69(s),153.46–153.25(m),150.00(s),147.34(d,J＝1.5Hz),139.73(s),138.06(s),136.56(s),134.53(s),131.50(s),129.78(s),129.48(s),127.24(s),126.54–126.33(m),123.69(s),117.94(s),112.64–112.24(m),110.56(s),110.01(s),108.38–108.16(m),101.78(s),72.77(s),69.29(s),65.32(s),56.89–56.58(m),52.02–51.63(m),50.51–50.20(m),45.72(s),43.76(s),40.52(s),17.27(s).
MS(ESI):816.0257for[M+H]+(calculated 816.3342for C40H37ClN4O13).。
d48化合物：2-(4-氯-2-硝基苯氧基)丙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
浅灰色固体；产率:55％；m.p.:125-127℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.18(s,1H),8.08–7.94(m,2H),7.66(s,1H),7.27(s,1H),6.99–6.85(m,2H),6.83(s,1H),6.74(s,1H),6.69–6.65(m,2H),5.92–5.88(m,2H),4.74(d,J＝18.8Hz,2H),4.37(s,1H),4.12(s,1H),3.88(s,1H),3.81–3.77(m,6H),3.66–3.61(m,4H),3.11(s,1H),2.90(t,J＝2.1Hz,3H),2.78–2.74(m,2H),1.77–1.65(m,3H).
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ176.26(s),172.71(s),158.69(s),153.46–153.25(m),149.72(s),147.34(d,J＝1.5Hz),139.73(s),138.06(s),136.95(s),133.58(s),131.50(s),129.78(s),129.48(s),126.61(s),126.54–126.33(m),126.11(s),120.76(s),112.64–112.24(m),110.56(s),110.01(s),108.38–108.16(m),101.78(s),72.77(s),69.29(s),65.32(s),56.89–56.58(m),52.02–51.63(m),50.51–50.20(m),45.72(s),43.76(s),40.52(s),17.27(s).
MS(ESI):816.0257for[M+H]+(calculated 816.3342for C40H37ClN4O13).。
d49化合物：2-(5-氯-2-硝基苯氧基)丙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d49化合物表征：
浅灰色固体；产率:55％；m.p.:136-138℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.08–7.94(m,3H),7.26(s,1H),7.21(s,1H),6.99–6.87(m,3H),6.80(s,1H),6.61–6.57(m,2H),5.92–5.88(m,2H),4.97(s,1H),4.76(s,1H),4.37(s,1H),4.12(s,1H),3.88(s,1H),3.80–3.76(m,6H),3.66–3.60(m,4H),3.54(s,1H),3.27(s,1H),2.92–2.88(m,2H),2.84–2.80(m,2H),1.82–1.70(m,3H).
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ176.26(s),172.71(s),158.69(s),153.34(t,J＝2.6Hz),147.34(d,J＝1.5Hz),139.73(s),139.07(s),138.06(s),134.47(s),131.50(s),130.18(s),129.78(s),129.48(s),126.54–126.33(m),123.20(s),119.47(s),112.64–112.24(m),110.56(s),110.01(s),108.38–108.16(m),101.78(s),72.77(s),69.29(s),65.32(s),56.89–56.58(m),52.02–51.63(m),50.51–50.20(m),45.72(s),43.76(s),40.52(s),17.27(s).
MS(ESI):816.0257for[M+H]+(calculated 816.3342for C40H37ClN4O13).。
d50化合物：2-(3-甲基-2-硝基苯氧基)丁酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d50化合物表征：
黄色固体；产率:53％；m.p.:142-144℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.10–7.96(m,26H),7.52(s,12H),6.98(dd,J＝26.8,15.7Hz,52H),6.90(s,13H),6.81(s,13H),6.51–6.47(m,25H),5.92–5.88(m,25H),4.76(s,13H),4.43(s,11H),4.37(s,15H),4.12(s,13H),3.99–3.72(m,92H),3.72(s,1H),3.71–3.67(m,25H),3.54–3.50(m,25H),3.40(s,10H),3.29(s,13H),2.84–2.80(m,25H),2.76–2.72(m,25H),2.41–2.37(m,38H),2.14(s,11H),2.06(s,11H),1.04–1.00(m,37H).
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ176.26(s),172.42(s),158.69(s),153.46–153.25(m),151.38(s),147.34(d,J＝1.5Hz),140.03(s),139.73(s),138.06(s),135.93(s),131.44(d,J＝15.9Hz),129.78(s),129.48(s),126.54–126.33(m),126.14(s),117.43(s),112.64–112.24(m),110.56(s),110.01(s),108.38–108.16(m),101.78(s),77.38(s),69.29(s),65.32(s),56.89–56.58(m),52.02–51.63(m),50.51–50.20(m),45.72(s),43.76(s),40.52(s),23.58(s),19.38(s),10.32(s).
MS(ESI):811.3543for[M+H]+(calculated 811.7857for C42H42N4O13).。
d51化合物：2-(4-甲基-2-硝基苯氧基)丁酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d51化合物表征：
黄色固体；产率:38％；m.p.:150-152℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.09–7.96(m,2H),7.94(s,1H),7.45(s,1H),7.04(s,1H),7.02–6.88(m,2H),6.81(s,1H),6.77(s,1H),6.62–6.58(m,2H),5.92–5.88(m,2H),4.76(s,1H),4.43(s,1H),4.37(s,1H),4.12(s,1H),3.88(s,1H),3.80–3.76(m,6H),3.69–3.65(m,2H),3.50–3.46(m,2H),3.02(s,1H),2.93(t,J＝4.4Hz,3H),2.66–2.62(m,2H),2.35–2.31(m,3H),2.15(s,1H),2.07(s,1H),1.05–1.01(m,3H).
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ176.26(s),172.42(s),158.69(s),153.46–153.25(m),148.90(s),147.34(d,J＝1.5Hz),139.73(s),139.45(s),138.06(s),132.50(s),132.07(s),131.50(s),129.78(s),129.48(s),126.54–126.20(m),116.70(s),112.64–112.24(m),110.56(s),110.01(s),108.38–108.16(m),101.78(s),77.38(s),69.29(s),65.32(s),56.89–56.58(m),52.02–51.63(m),50.51–50.20(m),45.72(s),43.76(s),40.52(s),23.58(s),21.39(s),10.32(s).
MS(ESI):811.3543for[M+H]+(calculated 811.7857for C42H42N4O13).。
d52化合物：2-(5-甲基-2-硝基苯氧基)丁酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d52化合物表征：
黄色固体；产率:47％；m.p.:112-114℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.09–7.89(m,3H),7.03(d,J＝19.9Hz,2H),6.99–6.88(m,2H),6.81(s,1H),6.77(s,1H),6.62–6.58(m,2H),5.92–5.88(m,2H),4.76(s,1H),4.43(s,1H),4.37(s,1H),4.12(s,1H),3.88(s,1H),3.80–3.76(m,6H),3.69–3.65(m,2H),3.50–3.46(m,2H),3.02(s,1H),2.93(t,J＝4.2Hz,3H),2.66–2.62(m,2H),2.37–2.33(m,3H),2.15(s,1H),2.07(s,1H),1.05–1.01(m,3H).
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ176.26(s),172.42(s),158.69(s),153.46–153.25(m),152.43(s),147.34(d,J＝1.5Hz),145.36(s),139.73(s),138.06(s),134.78(s),131.50(s),129.78(s),129.48(s),126.63(s),126.54–126.33(m),125.12(s),118.98(s),112.64–112.24(m),110.56(s),110.01(s),108.38–108.16(m),101.78(s),77.38(s),69.29(s),65.32(s),56.89–56.58(m),52.02–51.63(m),50.51–50.20(m),45.72(s),43.76(s),40.52(s),23.58(s),21.39(s),10.32(s).
MS(ESI):811.3543for[M+H]+(calculated 811.7857for C42H42N4O13).。
d53化合物：2-(3-甲氧基-2-硝基苯氧基)丁酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d53化合物表征：
黄色固体；产率:54％；m.p.:137-139℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.09–7.95(m,2H),7.61(s,1H),6.95(dd,J＝5.3,1.0Hz,4H),6.82(s,1H),6.78(s,1H),6.61–6.57(m,2H),5.92–5.88(m,2H),4.76(s,1H),4.43(s,1H),4.37(s,1H),4.12(s,1H),3.88(s,2H),3.81–3.76(m,8H),3.69–3.65(m,2H),3.53–3.49(m,2H),3.02(s,1H),2.89–2.85(m,2H),2.71(s,1H),2.67–2.63(m,2H),2.07(d,J＝4.0Hz,2H),1.05–1.01(m,3H).
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ176.26(s),172.42(s),158.69(s),155.74(s),153.88(s),153.46–153.25(m),147.34(d,J＝1.5Hz),139.73(s),138.06(s),132.97(s),131.50(s),129.78(s),129.48(s),129.02(s),126.54–126.33(m),112.64–112.24(m),111.67(s),111.07(s),110.56(s),110.01(s),108.38–108.16(m),101.78(s),77.38(s),69.29(s),65.32(s),56.89–56.58(m),52.02–51.63(m),50.51–50.20(m),45.72(s),43.76(s),40.52(s),23.58(s),10.32(s).
MS(ESI):827.2741for[M+H]+(calculated 827.8427for C42H42N4O14).。
d54化合物：2-(4-甲氧基-2-硝基苯氧基)丁酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d54化合物表征：
黄色固体；产率:50％；m.p.:122-124℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.10–7.95(m,2H),7.69(s,1H),7.20(d,J＝33.4Hz,2H),7.03–6.89(m,2H),6.77(d,J＝17.3Hz,2H),6.72–6.68(m,2H),5.92–5.88(m,2H),4.76(s,1H),4.43(s,1H),4.37(s,1H),4.12(s,1H),3.88(s,1H),3.86–3.80(m,9H),3.64–3.59(m,4H),3.22(s,1H),2.89(t,J＝8.8Hz,3H),2.83–2.79(m,2H),2.21(s,1H),2.08(s,1H),1.02–0.98(m,3H).
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ176.26(s),172.42(s),158.69(s),155.48(s),153.46–153.25(m),147.34(d,J＝1.5Hz),144.08(s),140.30(s),139.73(s),138.06(s),131.50(s),129.78(s),129.48(s),126.54–126.33(m),118.83(s),117.07(s),112.71(s),112.61–112.24(m),110.56(s),110.01(s),108.38–108.16(m),101.78(s),77.38(s),69.29(s),65.32(s),56.89–56.58(m),56.04(s),52.02–51.63(m),50.51–50.20(m),45.72(s),43.76(s),40.52(s),23.58(s),10.32(s).
MS(ESI):827.2741for[M+H]+(calculated 827.8427for C42H42N4O14).。
d55化合物：2-(5-甲氧基-2-硝基苯氧基)丁酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d55化合物表征：
黄色固体；产率:48％；m.p.:146-148℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.05–8.00(m,3H),7.02–6.90(m,2H),6.82(s,1H),6.79–6.73(m,3H),6.71–6.67(m,2H),5.92–5.88(m,2H),4.95(s,1H),4.76(s,1H),4.37(s,1H),4.12(s,1H),3.95–3.80(m,4H),3.80–3.76(m,6H),3.69–3.65(m,2H),3.53–3.49(m,2H),3.13(s,1H),2.90(t,J＝8.8Hz,3H),2.65–2.61(m,2H),2.18(s,1H),2.10(s,1H),1.01–0.97(m,3H).
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ176.26(s),172.42(s),163.94(s),158.69(s),154.60(s),153.46–153.25(m),147.34(d,J＝1.5Hz),139.73(s),138.06(s),131.50(s),131.33(s),129.78(s),129.48(s),128.23(s),126.54–126.33(m),112.64–112.24(m),110.56(s),110.01(s),108.69(s),108.38–108.16(m),104.75(s),101.78(s),77.38(s),69.29(s),65.32(s),56.89–56.58(m),56.04(s),52.02–51.63(m),50.51–50.20(m),45.72(s),43.76(s),40.52(s),23.58(s),10.32(s).
MS(ESI):827.2741for[M+H]+(calculated 827.8427for C42H42N4O14).。
d56化合物：2-(3-氟-2-硝基苯氧基)丁酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d56化合物表征：
红棕色固体；产率:38％；m.p.:157-159℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.09–7.95(m,2H),7.57(s,1H),6.93(dd,J＝22.4,3.1Hz,4H),6.81(s,1H),6.75(s,1H),6.64–6.60(m,2H),5.92–5.88(m,2H),4.76(s,1H),4.43(s,1H),4.37(s,1H),4.12(s,1H),3.88(s,1H),3.81–3.77(m,6H),3.69–3.65(m,2H),3.50–3.46(m,2H),3.02(s,1H),2.93(t,J＝5.2Hz,3H),2.66–2.62(m,2H),2.07(d,J＝3.3Hz,2H),1.05–1.01(m,3H).，
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ176.26(s),172.42(s),159.69(s),158.69(s),153.46–153.25(m),150.86(s),147.34(d,J＝1.5Hz),139.73(s),138.06(s),134.32(s),131.50(s),129.78(s),129.48(s),128.04(s),126.54–126.33(m),113.99(s),112.80(t,J＝66.4Hz),110.56(s),110.01(s),108.38–108.16(m),101.78(s),77.38(s),69.29(s),65.32(s),56.89–56.58(m),52.02–51.63(m),50.51–50.20(m),45.72(s),43.76(s),40.52(s),23.58(s),10.32(s).
MS(ESI):815.2520for[M+H]+(calculated 815.2677for C41H39FN4O13).。
d57化合物：2-(4-氟-2-硝基苯氧基)丁酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
红棕色固体；产率:55％；m.p.:125-127℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.09–7.95(m,2H),7.81(s,1H),7.33(s,1H),7.08(s,1H),7.02–6.88(m,2H),6.81(s,1H),6.77(s,1H),6.59–6.55(m,2H),5.92–5.88(m,2H),4.76(s,1H),4.43(s,1H),4.37(s,1H),4.12(s,1H),3.88(s,1H),3.80–3.76(m,6H),3.69–3.65(m,2H),3.49–3.45(m,2H),3.03(s,1H),2.93(t,J＝4.0Hz,3H),2.66–2.62(m,2H),2.15(s,1H),2.07(s,1H),1.05–1.01(m,3H).
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ176.26(s),172.42(s),158.69(s),156.99(s),153.46–153.25(m),147.57(s),147.34(d,J＝1.5Hz),139.73(s),138.06(s),136.40(s),131.50(s),129.78(s),129.48(s),126.54–126.33(m),121.47(s),121.20(s),112.88(t,J＝81.2Hz),112.43–112.24(m),110.56(s),110.01(s),108.38–108.16(m),101.78(s),77.38(s),69.29(s),65.32(s),56.89–56.58(m),52.02–51.63(m),50.51–50.20(m),45.72(s),43.76(s),40.52(s),23.58(s),10.32(s).
MS(ESI):815.2520for[M+H]+(calculated 815.2677for C41H39FN4O13).。
d58化合物：2-(5-氟-2-硝基苯氧基)丁酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d58化合物表征：
红棕色固体；产率:55％；m.p.:136-138℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.04–7.98(m,3H),7.02–6.83(m,4H),6.81(s,1H),6.76(s,1H),6.59–6.55(m,2H),5.92–5.88(m,2H),4.76(s,1H),4.43(s,1H),4.37(s,1H),4.12(s,1H),3.88(s,1H),3.81–3.77(m,6H),3.69–3.65(m,2H),3.49–3.45(m,2H),3.03(s,1H),2.93(t,J＝4.4Hz,3H),2.66–2.62(m,2H),2.15(s,1H),2.07(s,1H),1.05–1.01(m,3H).
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ176.26(s),168.42(d,J＝1000.3Hz),158.69(s),154.21(s),153.46–153.25(m),147.34(d,J＝1.5Hz),139.73(s),138.06(s),131.50(s),129.83(d,J＝13.6Hz),129.47(d,J＝1.2Hz),126.54–126.33(m),112.64–112.24(m),110.81(s),110.56(s),110.01(s),108.38–108.16(m),107.33(s),101.78(s),77.38(s),69.29(s),65.32(s),56.89–56.58(m),52.02–51.63(m),50.51–50.20(m),45.72(s),43.76(s),40.52(s),23.58(s),10.32(s).
MS(ESI):815.2520for[M+H]+(calculated 815.2677for C41H39FN4O13).。
d59化合物：2-(3-溴-2-硝基苯氧基)丁酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d59化合物表征：
棕色固体；产率:53％；m.p.:162-164℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.09–7.95(m,2H),7.51(s,1H),7.43(s,1H),7.18(s,1H),7.02–6.88(m,2H),6.81(s,1H),6.77(s,1H),6.64–6.60(m,2H),5.92–5.88(m,2H),4.76(s,1H),4.43(s,1H),4.37(s,1H),4.12(s,1H),3.88(s,1H),3.79–3.75(m,6H),3.69–3.65(m,2H),3.50–3.46(m,2H),3.01(s,1H),2.93(t,J＝4.0Hz,3H),2.66–2.62(m,2H),2.07(d,J＝13.7Hz,2H),1.04–1.00(m,3H).
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ176.26(s),172.42(s),158.69(s),153.46–153.25(m),152.84(s),147.34(d,J＝1.5Hz),139.73(s),139.13(s),138.06(s),136.49(s),131.50(s),129.78(s),129.48(s),126.54–126.33(m),125.27(s),118.87(d,J＝18.8Hz),112.64–112.24(m),110.56(s),110.01(s),108.38–108.16(m),101.78(s),77.38(s),69.29(s),65.32(s),56.89–56.58(m),52.02–51.63(m),50.51–50.20(m),45.72(s),43.76(s),40.52(s),23.58(s),10.32(s).
MS(ESI):875.1741for[M+H]+(calculated 875.2057for C41H39BrN4O13).。
d60化合物：2-(4-溴-2-硝基苯氧基)丁酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d60化合物表征：
棕色固体；产率:49％；m.p.:158-160℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.26(s,1H),8.09–7.95(m,2H),7.76(s,1H),7.08–6.88(m,3H),6.81(s,1H),6.77(s,1H),6.59–6.55(m,2H),5.92–5.88(m,2H),4.76(s,1H),4.43(s,1H),4.37(s,1H),4.12(s,1H),3.88(s,1H),3.80–3.76(m,6H),3.69–3.65(m,2H),3.49–3.45(m,2H),3.03(s,1H),2.93(t,J＝4.0Hz,3H),2.66–2.62(m,2H),2.15(s,1H),2.06(s,1H),1.04–1.00(m,3H).
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ176.26(s),172.42(s),158.69(s),153.46–153.25(m),152.32(s),147.34(d,J＝1.5Hz),139.73(s),138.03(d,J＝7.7Hz),136.15(s),131.50(s),130.02(s),129.78(s),129.48(s),126.54–126.33(m),120.86(s),117.90(s),112.64–112.24(m),110.56(s),110.01(s),108.38–108.16(m),101.78(s),77.38(s),69.29(s),65.32(s),56.89–56.58(m),52.02–51.63(m),50.51–50.20(m),45.72(s),43.76(s),40.52(s),23.58(s),10.32(s).
MS(ESI):875.1741for[M+H]+(calculated 875.2057for C41H39BrN4O13).。
d61化合物：2-(5-溴-2-硝基苯氧基)丁酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d61化合物表征：
棕色固体；产率:46％；m.p.:146-148℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.09–8.02(m,1H),7.93(s,2H),7.36(s,1H),7.31(s,1H),7.02–6.88(m,2H),6.81(s,1H),6.77(s,1H),6.63–6.59(m,2H),5.92–5.88(m,2H),4.76(s,1H),4.43(s,1H),4.37(s,1H),4.12(s,1H),3.88(s,1H),3.80–3.76(m,6H),3.69–3.65(m,2H),3.50–3.46(m,2H),3.03(s,1H),2.93(t,J＝5.7Hz,3H),2.66–2.62(m,2H),2.15(s,1H),2.07(s,1H),1.05–1.01(m,3H).
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ176.26(s),172.42(s),158.69(s),154.40(s),153.46–153.25(m),147.34(d,J＝1.5Hz),139.73(s),138.06(s),135.67(s),131.50(s),131.18(s),129.78(s),129.48(s),128.68(s),126.54–126.33(m),124.78(s),121.25(s),112.64–112.24(m),110.56(s),110.01(s),108.38–108.16(m),101.78(s),77.38(s),69.29(s),65.32(s),56.89–56.58(m),52.02–51.63(m),50.51–50.20(m),45.72(s),43.76(s),40.52(s),23.58(s),10.32(s).
MS(ESI):875.1741for[M+H]+(calculated 875.2057for C41H39BrN4O13).。
d62化合物：2-(3-氯-2-硝基苯氧基)丁酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d62化合物表征：
浅灰色固体；产率:43％；m.p.:136-138℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.09–7.95(m,2H),7.56(s,1H),7.27(s,1H),7.13(s,1H),7.02–6.88(m,2H),6.79(d,J＝19.2Hz,2H),6.58–6.54(m,2H),5.92–5.88(m,2H),4.76(s,1H),4.43(s,1H),4.37(s,1H),4.12(s,1H),3.88(s,1H),3.79–3.75(m,6H),3.69–3.65(m,2H),3.50–3.46(m,2H),3.01(s,1H),2.93(t,J＝3.6Hz,3H),2.66–2.62(m,2H),2.07(d,J＝12.8Hz,2H),1.04–1.00(m,3H).
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ176.26(s),172.42(s),158.69(s),153.46–153.25(m),150.33(s),147.34(d,J＝1.5Hz),139.73(s),138.06(s),136.44(s),134.39(s),131.50(s),129.78(s),129.48(s),126.86(s),126.54–126.33(m),123.85(s),117.84(s),112.64–112.24(m),110.56(s),110.01(s),108.38–108.16(m),101.78(s),77.38(s),69.29(s),65.32(s),56.89–56.58(m),52.02–51.63(m),50.51–50.20(m),45.72(s),43.76(s),40.52(s),23.58(s),10.32(s).
MS(ESI):831.2220for[M+H]+(calculated 831.2801for C41H39ClN4O13).。
d63化合物：2-(4-氯-2-硝基苯氧基)丁酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d63化合物表征：
浅灰色固体；产率:45％；m.p.:125-127℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.10(s,1H),8.08–7.95(m,2H),7.60(s,1H),7.04(s,1H),7.02–6.88(m,2H),6.81(s,1H),6.77(s,1H),6.59–6.55(m,2H),5.92–5.88(m,2H),4.76(s,1H),4.43(s,1H),4.37(s,1H),4.12(s,1H),3.88(s,1H),3.80–3.76(m,6H),3.69–3.65(m,2H),3.49–3.45(m,2H),3.03(s,1H),2.93(t,J＝4.0Hz,3H),2.66–2.62(m,2H),2.15(s,1H),2.06(s,1H),1.04–1.00(m,3H).
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ176.26(s),172.42(s),158.69(s),153.46–153.25(m),150.10(s),147.34(d,J＝1.5Hz),139.73(s),138.06(s),136.99(s),133.72(s),131.50(s),129.78(s),129.48(s),126.73–126.33(m),126.02(s),120.84(s),112.64–112.24(m),110.56(s),110.01(s),108.38–108.16(m),101.78(s),77.38(s),69.29(s),65.32(s),56.89–56.58(m),52.02–51.63(m),50.51–50.20(m),45.72(s),43.76(s),40.52(s),23.58(s),10.32(s).
MS(ESI):831.2220for[M+H]+(calculated 831.2801for C41H39ClN4O13).。
d64化合物：2-(5-氯-2-硝基苯氧基)丁酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
d64化合物表征：
浅灰色固体；产率:49％；m.p.:119-121℃；1H NMR(400MHz,DMSO-d6,TMS,ppm):δ8.13–7.89(m,3H),7.20(s,1H),7.15(s,1H),7.02–6.88(m,2H),6.81(s,1H),6.77(s,1H),6.62–6.58(m,2H),5.92–5.88(m,2H),4.76(s,1H),4.43(s,1H),4.37(s,1H),4.12(s,1H),3.88(s,1H),3.80–3.76(m,6H),3.69–3.65(m,2H),3.50–3.46(m,2H),3.02(s,1H),2.93(t,J＝4.8Hz,3H),2.66–2.62(m,2H),2.15(s,1H),2.07(s,1H),1.05–1.01(m,3H).
13C NMR(100MHz,DMSO-d6,TMS,ppm):δ176.26(s),172.42(s),158.69(s),153.58(s),153.46–153.25(m),147.34(d,J＝1.5Hz),139.73(s),138.96(s),138.06(s),134.44(s),131.50(s),130.04(s),129.78(s),129.48(s),126.54–126.33(m),123.38(s),119.48(s),112.64–112.24(m),110.56(s),110.01(s),108.38–108.16(m),101.78(s),77.38(s),69.29(s),65.32(s),56.89–56.58(m),52.02–51.63(m),50.51–50.20(m),45.72(s),43.76(s),40.52(s),23.58(s),10.32(s).
MS(ESI):831.2220for[M+H]+(calculated 831.2801for C41H39ClN4O13).。
二.体外细胞试验
本发明的64个化合物均表现出搞肿瘤的药理活性，但效果不一，以下给出具有最佳活性的化合物的实验结果。
(1)实验材料
细胞株：A-549(人非小细胞肺癌细胞株)，HeLa(人宫颈癌细胞株)，Hep-G2(人肝癌细胞株)，WI-38(人胚肺成纤维细胞)
培养基：Hyclone RPMI-1640培养基，DMEM高糖培养基，10％胎牛血清。
药物及配制：目标化合物，溶于DMSO,并按一定比例稀释得到5个浓度。
(2)实验方法
将对数期生长的细胞株，以每孔约103个细胞加入96孔板中，待细胞贴壁后将不同浓度的溶液加入作用，每个浓度设置3个复孔。培养箱中培养48h，每孔加入10μL浓度为5mg/mL的MTT溶液，继续培养4h后弃去上清液，每孔再加入150μL DMSO，充分震荡使甲瓒溶解，在酶标仪570nm下测定吸光度OD值。细胞抑制率的计算公式为：
细胞抑制率％＝(对照组OD值-用药组OD值)/对照组OD值×100％，再计算出IC50。
(3)实验结果
表3目标化合物化对不同细胞株的抑制作用
由表1可知，本发明的四类化合物(即前述的衍生物)对A-549(1.19μM≤IC50≤30.46μM)、Hela(0.77μM≤IC50≤23.21μM)和Hep-G2(0.83μM≤IC50≤30.68μM)三种肿瘤细胞都有一定的增殖抑制作用，其中对A-549和Hela的增殖抑制效果相当，相对而言对Hep-G2抑制效果稍差；
药物释放体系供电子效应组(0.77μM≤IC50≤22.92μM)对3种肿瘤细胞抑制效果强于吸电子效应组(5.49μM≤IC50≤28.63μM)、空间效应组(4.80μM≤IC50≤30.68μM)和综合效应组(14.35μM≤IC50≤30.46μM)；
供电子组的两个化合物d2化合物：2-(4-甲基-2-硝基苯氧基)乙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯(0.77μM≤IC50≤1.19μM)和d5化合物：2-(4-甲氧基-2-硝基苯氧基)乙酸-4β-N-(4-硝基苯基哌嗪)-4′-去氧表鬼臼毒素酯，
(0.91μM≤IC50≤1.58μM)对3种肿瘤细胞均表现出很好的抗肿瘤增殖活性，和阳性对照VP-16(1.42μM≤IC50≤2.64μM)相当；优于阳性对照DEPPT(9.64μM≤IC50≤15.29μM)；
综合效应组相当于空间效应组和供电子效应组以及吸电子效应组结构的叠加，对肿瘤细胞的抑制作用不如供电子效应组和吸电子效应组，但仍具有一定的抑制效果。

Claims (9)

1.一种如式Ⅰ示邻硝基芳酰化衍生物类化合物，
其中：取代基R1为氢、氟、氯、溴、甲基或甲氧基；取代基R2为氢、甲基、乙基或二甲基。
2.权利要求1所述的邻硝基芳酰化衍生物类化合物的制备方法，其特征在于通过反应式Ⅱ所示的方法制备，即：
1)将化合物a和无水碳酸钾加入溶剂DMF中，并充分搅拌，再将化合物b滴加到前述反应液中，加入催化量KI，在80～100℃搅拌充分反应，反应结束后分离出滤液，除去溶液DMF，残余物中加入NaOH至完全水解，再在其中滴加浓盐酸至固体不在析出，分离出滤渣用pH＝2～3盐酸水溶液冲洗，得到化合物c；
2)称取前一步骤得到的c，溶于干燥四氢呋喃中，加SOCl2和吡啶后70℃回流，旋蒸掉溶剂及过量SOCl2，得到酰氯，密封备用；
3)将4β-N-[(4-硝基苯基)哌嗪]-4′-去甲基表鬼臼毒素和三乙胺加入到干燥四氢呋喃中；在-20℃将步骤2)得到的酰氯缓慢滴加到前述四氢呋喃中，剧烈搅拌并在室温下充分反应后抽滤，滤液浓缩，所得残留物溶于二氯甲烷，分别用稀醋酸溶液，稀碳酸钠溶液以及饱和氯化钠溶液洗涤，合并有机层用无水NaSO4干燥，然后过滤，滤液经浓缩处理后用硅胶柱层析纯化，得到目标化合物d。
3.根据权利要求2所述的邻硝基芳酰化衍生物类化合物的制备方法，其特征在于：
步骤1)中是将10mmol化合物a和无水碳酸钾加入溶剂DMF中，并充分搅拌，再将12～15mmol化合物b滴加到前述反应液中，进行反应；
步骤2)中称取1.2mmol干燥化合物c溶于10mL干燥的四氢呋喃中，并向其中滴加两滴吡啶，然后缓慢的将3mmol的氯化亚砜滴入其中；
步骤3)中滤液用硅胶柱层析纯化时是以体积比为300/100/1的石油醚/乙酸乙酯/乙腈为洗脱剂。
4.权利要求2或3所述的邻硝基芳酰化衍生物类化合物的制备方法，其特征在于：在冰浴条件下，将干燥的三甲基氯硅烷溶于无水乙腈后缓慢滴加到含去甲基表鬼臼毒素与碘化钠的无水乙睛中，经搅拌后加入无水碳酸钡再充分搅拌加入无水三乙胺数滴至反应液呈碱性后，加入化合物1-(4-硝基苯基)哌嗪，室温搅拌反应，反应完毕抽滤，滤液经浓缩处理，残留物中加入硫代硫酸钠溶液，用乙酸乙酯萃取，合并的有机层用无水硫酸钠干燥，然后过滤，滤液浓缩处理后经硅胶柱层析法纯化，以体积比为200/100/1的正己烷/乙酸乙酯/三乙胺为洗脱剂，得到化合物4β-N-[(4-硝基苯基)哌嗪]-4′-去甲基表鬼臼毒素。
5.权利要求1所述的邻硝基芳酰化衍生物类化合物在制备拓朴异构酶抑制剂药物中的应用。
6.权利要求1所述的邻硝基芳酰化衍生物类化合物在制备抗肿瘤药物中的应用。
7.权利要求1所述的邻硝基芳酰化衍生物类化合物在制备抗人非小细胞肺癌药物中的应用。
8.权利要求1所述的邻硝基芳酰化衍生物类化合物在制备抗人宫颈癌药物中的应用。
9.权利要求1所述的邻硝基芳酰化衍生物类化合物在制备抗人肝癌药物中的应用。
CN201711027851.5A 2017-10-28 2017-10-28 一种邻硝基芳酰化衍生物类化合物、制备方法及其应用 Withdrawn CN107964014A (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201711027851.5A CN107964014A (zh) 2017-10-28 2017-10-28 一种邻硝基芳酰化衍生物类化合物、制备方法及其应用

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201711027851.5A CN107964014A (zh) 2017-10-28 2017-10-28 一种邻硝基芳酰化衍生物类化合物、制备方法及其应用

Publications (1)

Publication Number Publication Date
CN107964014A true CN107964014A (zh) 2018-04-27

Family

ID=61999839

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201711027851.5A Withdrawn CN107964014A (zh) 2017-10-28 2017-10-28 一种邻硝基芳酰化衍生物类化合物、制备方法及其应用

Country Status (1)

Country Link
CN (1) CN107964014A (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115990165A (zh) * 2022-12-16 2023-04-21 安徽工业大学 一种鬼臼毒素衍生物在治疗三阴性乳腺癌药物中的应用

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5643885A (en) * 1992-12-22 1997-07-01 Pierre Fabre Medicament Etoposide derivatives, process for preparing them, their use as a medicinal product and their use for the preparation of a medicinal product intended for anti-cancer treatment
CN1437604A (zh) * 2000-06-20 2003-08-20 瑟维尔实验室 鬼臼毒素氨基甲酸酯和硫代氨基甲酸酯衍生物及其制备方法和含有它们的药物组合物
CN1850828A (zh) * 2006-05-26 2006-10-25 华东理工大学 一种鬼臼毒素的衍生物及其制备方法
CN102070645A (zh) * 2011-01-07 2011-05-25 兰州大学 一种脱氧鬼臼毒素类化合物及其制备与应用
CN102675140A (zh) * 2012-05-30 2012-09-19 兰州大学 一种邻硝基芳酰氮芥衍生物的制备及用途
CN103553973A (zh) * 2013-05-16 2014-02-05 兰州纬易生物科技开发有限责任公司 邻硝基芳酰基β-氯乙基亚硝基脲类化合物及制备和用途
CN107915736A (zh) * 2017-11-28 2018-04-17 兰州大学 邻硝基芳酰化衍生物类化合物、制备方法及其应用

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5643885A (en) * 1992-12-22 1997-07-01 Pierre Fabre Medicament Etoposide derivatives, process for preparing them, their use as a medicinal product and their use for the preparation of a medicinal product intended for anti-cancer treatment
CN1437604A (zh) * 2000-06-20 2003-08-20 瑟维尔实验室 鬼臼毒素氨基甲酸酯和硫代氨基甲酸酯衍生物及其制备方法和含有它们的药物组合物
CN1850828A (zh) * 2006-05-26 2006-10-25 华东理工大学 一种鬼臼毒素的衍生物及其制备方法
CN102070645A (zh) * 2011-01-07 2011-05-25 兰州大学 一种脱氧鬼臼毒素类化合物及其制备与应用
CN102675140A (zh) * 2012-05-30 2012-09-19 兰州大学 一种邻硝基芳酰氮芥衍生物的制备及用途
CN103553973A (zh) * 2013-05-16 2014-02-05 兰州纬易生物科技开发有限责任公司 邻硝基芳酰基β-氯乙基亚硝基脲类化合物及制备和用途
CN107915736A (zh) * 2017-11-28 2018-04-17 兰州大学 邻硝基芳酰化衍生物类化合物、制备方法及其应用

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
JIAN-FEI LIU等: "Synthesis and evaluation of the cell cycle arrest and CT DNA interaction properties of 4β-amino-4’-O-demethyl-4-deoxypodophyllotoxins", 《BIOORG. MED. CHEM. 》 *
汪丽: "鬼臼毒素衍生物的设计、合成及抗肿瘤活性研究", 《中国优秀硕士学位论文全文数据库-医药卫生科技辑》 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115990165A (zh) * 2022-12-16 2023-04-21 安徽工业大学 一种鬼臼毒素衍生物在治疗三阴性乳腺癌药物中的应用

Similar Documents

Publication Publication Date Title
CN106632043A (zh) 一类具抗肿瘤活性的甘草查尔酮a二氢吡唑类衍生物及其合成方法
CN109293574A (zh) 一类具有抗肿瘤活性的脱氢枞酸芳胺基苯并咪唑衍生物及其制备方法和应用
CN110078695B (zh) 一种槲皮素衍生物及其制备方法
CN107964014A (zh) 一种邻硝基芳酰化衍生物类化合物、制备方法及其应用
CN102382164B (zh) 蟾蜍内酰胺类化合物及其制备方法与应用
CN109776554B (zh) 二氢色原酮拼接吡咯螺环氧化吲哚化合物及其制备方法及应用
CN110655506B (zh) 一种替加氟的制备方法
CN109251196B (zh) 氨基苯并[d]氮杂*基喹唑啉类化合物及其制备方法和应用
CN101671329A (zh) 3-氨基醇取代的吲哚马来酰亚胺化合物、其制备和应用
CN105367575B (zh) 一种叶酸类化合物、其制备方法及医药用途
CN108014113A (zh) 丁酰氨基二甲氧基苯并[d]氮杂*基喹唑啉类化合物在制备治疗宫颈癌药物中的应用
CN104098524B (zh) 1-间甲氧基苯甲酰基-3-苯基-1,4-二氢-1,2,4,5-四嗪及制备和应用
CN108484623B (zh) 喜树碱衍生物及其制备方法与应用
CN108276420B (zh) 一种8,13-二氢苯并[5,6]色烯并[2,3-b]吲哚类化合物及其合成方法
CN109369772B (zh) 一种菲啶类两面针碱衍生物的合成方法及抗肿瘤应用
CN113321673A (zh) 一种新白叶藤碱硼酸类化合物的制备方法和用途
CN108329300B (zh) 硝基苯并[d]氮杂*基喹唑啉类化合物及其制备方法和应用
CN108125962B (zh) 苯并[d]氮杂*基喹唑啉类化合物在制备治疗肺癌药物中的应用
CN105949139A (zh) 一种仲丁基二苯基四嗪甲酰胺化合物及制备和应用
CN112300118A (zh) 一种新型苯并噻喃二酮化合物及其制备方法和应用
CN106588984B (zh) 一种6-磷酰基取代菲啶类衍生物的制备方法
CN101475563B (zh) 3-氨基-4-吲哚-n-甲基马来酰亚胺化合物、其制备及应用
CN115417857B (zh) 一种中药八角枫中的哌啶类生物碱及其提取纯化、半合成方法和应用
CN108484629A (zh) 一种青蒿琥酯衍生物及其合成方法及应用
CN116217611B (zh) 一种环丁酮衍生物及制备方法、用途

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
WW01 Invention patent application withdrawn after publication
WW01 Invention patent application withdrawn after publication

Application publication date: 20180427